N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists

ABSTRACT

A method for treating and/or preventing polycystic ovary syndrome (PCOS) including the administration, to a patient in need thereof, of a pharmaceutically effective amount of a compound of Formula I 
                         
or a pharmaceutically acceptable solvate thereof.

RELATED APPLICATION INFORMATION

This application is a continuation of U.S. patent application Ser. No.16/204,390, filed Nov. 29, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/796,028, filed Oct. 27, 2017, which is acontinuation-in-part of U.S. patent application Ser. No. 15/371,600,filed Dec. 7, 2016, which is a continuation-in-part of U.S. patentapplication Ser. No. 15/205,304, filed Jul. 8, 2016, which is acontinuation of U.S. patent application Ser. No. 14/694,228, filed Apr.23, 2015, which is a continuation-in-part of International ApplicationNo.: PCT/EP2014/056367, filed Mar. 28, 2014, which claims priority fromEP Application No.: 14154303.3, filed Feb. 7, 2014; EP Application No.:13193025.7, filed Nov. 15, 2013; and EP Application No.: 13161863.9,filed Mar. 29, 2013. The entire contents of these applications areincorporated herein by reference in their entirety.

FIELD OF INVENTION

The present invention relates to novelN-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazinesincluding their pharmaceutically acceptable solvates that are selectiveantagonists to neurokinin-3 receptor (NK-3) and are useful astherapeutic compounds, particularly in the treatment and/or preventionof a broad array of CNS and peripheral diseases or disorders.

BACKGROUND OF INVENTION

Tachykinin receptors are the targets of a family of structurally relatedpeptides which include substance P (SP), neurokinin A (NKA) andneurokinin B (NKB), named collectively “tachykinins”. Tachykinins aresynthesized in the central nervous system (CNS) and peripheral tissues,where they exert a variety of biological activities. Three tachykininreceptors are known which are named neurokinin-1 (NK-1), neurokinin-2(NK-2) and neurokinin-3 (NK-3) receptors. Tachykinin receptors belong tothe rhodopsin-like seven membrane G-protein coupled receptors. SP hasthe highest affinity and is believed to be the endogenous ligand ofNK-1, NKA for NK-2 receptor and NKB for NK-3 receptor, althoughcross-reactivity amongst these ligands does exist. The NK-1, NK-2 andNK-3 receptors have been identified in different species. NK-1 and NK-2receptors are expressed in a wide variety of peripheral tissues and NK-1receptors are also expressed in the CNS; whereas NK-3 receptors areprimarily expressed in the CNS.

The neurokinin receptors mediate a variety of tachykinin-stimulatedbiological effects that include transmission of excitatory neuronalsignals in the CNS and periphery (e.g. pain), modulation of smoothmuscle contractile activity, modulation of immune and inflammatoryresponses, induction of hypotensive effects via dilatation of theperipheral vasculature and stimulation of endocrine and exocrine glandsecretions.

In the CNS, the NK-3 receptor is expressed in regions including themedial prefrontal cortex, the hippocampus, the thalamus and theamygdala. Moreover, NK-3 receptors are expressed on dopaminergicneurons. Activation of NK-3 receptors has been shown to modulatedopamine, acetylcholine and serotonin release suggesting a therapeuticutility for NK-3 receptor modulators for the treatment of a variety ofdisorders including psychotic disorders, anxiety, depression,schizophrenia as well as obesity, pain or inflammation (Giardina et al.,Exp. Opinion Ther. Patents, 2000, 10(6), 939-960; Current Opinion inInvestigational Drugs, 2001, 2(7), 950-956 and Dawson and Smith, CurrentPharmaceutical Design, 2010, 16, 344-357).

Schizophrenia is classified into subgroups. The paranoid type ischaracterized by delusions and hallucinations and absence of thoughtdisorder, disorganized behavior, and affective flattening. In thedisorganized type, which is also named ‘hebephrenic schizophrenia’ inthe International Classification of Diseases (ICD), thought disorder andflat affect are present together. In the catatonic type, prominentpsychomotor disturbances are evident, and symptoms may include catatonicstupor and waxy flexibility. In the undifferentiated type, psychoticsymptoms are present but the criteria for paranoid, disorganized, orcatatonic types have not been met. The symptoms of schizophrenianormally manifest themselves in three broad categories, i.e. positive,negative and cognitive symptoms. Positive symptoms are those, whichrepresent an “excess” of normal experiences, such as hallucinations anddelusions. Negative symptoms are those where the patient suffers from alack of normal experiences, such as anhedonia and lack of socialinteraction. The cognitive symptoms relate to cognitive impairment inschizophrenics, such as a lack of sustained attention and deficits indecision making. The current antipsychotic drugs (APDs) are fairlysuccessful in treating the positive symptoms but fare less well for thenegative and cognitive symptoms. Contrary to that, NK-3 antagonists havebeen shown clinically to improve on both positive and negative symptomsin schizophrenics (Meltzer et al, Am. J. Psychiatry, 2004, 161, 975-984)and ameliorate cognitive behavior of schizophrenics (Curr. Opion.Invest. Drug, 2005, 6, 717-721).

In rat, morphological studies provide evidence for putative interactionsbetween NKB neurons and the hypothalamic reproductive axis (Krajewski etal, J. Comp. Neurol., 2005, 489(3), 372-386). In arcuate nucleusneurons, NKB expression co-localizes with estrogen receptor α anddynorphin, implicated in progesterone feedback to Gonadotropin ReleasingHormone (GnRH) secretion (Burke et al., J. Comp. Neurol., 2006, 498(5),712-726; Goodman et al., Endocrinology, 2004, 145(6), 2959-2967).Moreover, NK-3 receptor is highly expressed in the hypothalamic arcuatenucleus in neurons which are involved in the regulation of GnRH release.

WO 00/43008 discloses a method of suppressing gonadotropin and/orandrogen production with specific NK-3 receptor antagonists. Moreparticularly, the WO 00/43008 application relates to loweringluteinizing hormone (LH) blood level by administering an NK-3 receptorantagonist. Concurrently or alternatively with gonadotropin suppression,WO 00/43008 also relates to suppression of androgen production with NK-3receptor antagonists. Recently it has been postulated that NKB actsautosynaptically on kisspeptin neurons in the arcuate nucleus tosynchronize and shape the pulsatile secretion of kisspeptin and drivethe release of GnRH from fibers in the median eminence (Navarro et al.,J. of Neuroscience, 2009, 23(38), 11859-11866). All these observationssuggest a therapeutic utility for NK-3 receptor modulators for sexhormone-dependent diseases.

NK-3 receptors are also found in the human myenteric and submucosalplexus of the sigmoid colon as well as in the gastric fundus (Dass etal., Gastroenterol., 2002, 122 (Suppl 1), Abstract M1033) withparticular expression noted on myenteric intrinsic primary afferentneurons (IPANs) (Lomax and Furness, Cell Tissue Res, 2000, 302, 59-3).Intense stimulation of IPANs changes patterns of intestinal motility andintestinal sensitivity. Electrophysiology experiments have shown thatactivation of the NK-3 receptor changes the voltage threshold of actionpotentials in IPANs and promotes the generation of long-lasting plateaupotentials (Copel et al., J Physiol, 2009, 587, 1461-1479) that maysensitize these neurons to mechanical and chemical stimuli leading toeffects on gut motility and secretion. Similarly, Irritable BowelSyndrome (IBS) is characterized by patient hypersensitivity tomechanical and chemical stimuli. Thus, NK-3 antagonists have been testedin preclinical models of IBS where they have been shown to be effectiveto reduce nociceptive behavior caused by colo-rectal distension(Fioramonti et al., Neurogastroenterol Motil, 2003, 15, 363-369; Shaftonet al., Neurogastroenterol Motil, 2004, 16, 223-231) and, on this basis,NK-3 antagonists have been advanced into clinical development for thetreatment of IBS (Houghton et al., Neurogastroenterol Motil, 2007, 19,732-743; Dukes et al., Gastroenterol, 2007, 132, A60).

Non-peptide antagonists have been developed for each of the tachykininreceptors. Some of them have been described as dual modulators able tomodulate both NK-2 and NK-3 receptors (WO 06/120478). However, knownnon-peptide NK-3 receptor antagonists suffer from a number of drawbacks,notably poor safety profile and limited CNS penetrability that may limitthe success of these compounds in clinical development.

On this basis, new potent and selective antagonists of NK-3 receptor maybe of therapeutic value for the preparation of drugs useful in thetreatment and/or prevention of CNS and peripheral diseases or disordersin which NKB and the NK-3 receptors are involved.

Target potency alone, which may be demonstrated by competitive bindingdata, is not sufficient for drug development. Rather, efficacy in vivois contingent upon achieving a relevant “free” drug concentrationrelative to the target potency at the physiological site of action. Drugmolecules typically bind reversibly to proteins and lipids in plasma.The “free” fraction refers to the drug concentration that is unbound andtherefore available to engage the biological target and elicitpharmacological activity. This free fraction is commonly determinedusing plasma protein binding (PPB) assays. The free drug fraction isrelevant to not only achieving the desired pharmacological activity, butalso potentially undesirable activities including rapid hepaticmetabolism (leading to high first-pass clearance and thereby poor oralbioavailability) as well as possible off-target activities that can leadto safety concerns (for example, inhibition of hERG ion channelactivity, a widely accepted marker of cardiovascular toxicity).

The invention thus encompasses compounds of general Formula I, theirpharmaceutically acceptable solvates as well as methods of use of suchcompounds or compositions comprising such compounds as antagonists tothe NK-3 receptor. Compounds of Formula I areN-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines.The compounds of the invention are generally disclosed in internationalpatent application WO2011/121137 but none is specifically exemplifiedtherein. On another hand, unsubstituted and thus non-chiral5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines have been disclosed inWO2010/125102 as modulators of an unrelated target, namely P2X7.

SUMMARY OF THE INVENTION

In a general aspect, the invention provides compounds of general FormulaI:

and pharmaceutically acceptable solvates thereof, wherein:

-   -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl, nitrile or R³ is        thiophen-2-yl under the condition that R⁵ is not methyl;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl or fluoromethyl;    -   X¹ is N and X² is S or O; or X¹ is S and X² is N;    -   represents a single or a double bound depending on X¹ and X²;    -   stands for the (R)-enantiomer or for the racemate of compound of        Formula I.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising at least one compound according to the inventionor a pharmaceutically acceptable solvate thereof.

The invention also relates to the use of the above compounds or theirpharmaceutically acceptable solvates as modulators of NK-3 receptors,preferably as antagonists of NK-3 receptors.

The invention also relates to the use of the above compounds or theirpharmaceutically acceptable solvates as lowering agents of thecirculating LH levels.

The invention further provides methods of treatment and/or prevention ofdepression, anxiety, psychosis, schizophrenia, psychotic disorders,bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer'sdisease, attention deficit hyperactivity disorder (ADHD), pain,convulsion, obesity, inflammatory diseases including irritable bowelsyndrome (IBS) and inflammatory bowel disorders, emesis, pre-eclampsia,airway related diseases including chronic obstructive pulmonary disease,asthma, airway hyperresponsiveness, bronchoconstriction and cough,reproduction disorders, contraception and sex hormone-dependent diseasesincluding but not limited to benign prostatic hyperplasia (BPH),prostatic hyperplasia, metastatic prostatic carcinoma, testicularcancer, breast cancer, ovarian cancer, androgen dependent acne, malepattern baldness, endometriosis, abnormal puberty, uterine fibrosis,uterine fibroid tumor, hormone-dependent cancers, hyperandrogenism,hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrualdysphoric disease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulinresistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-ANwith hyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosiscomprising the administration of a therapeutically effective amount of acompound or pharmaceutically acceptable solvate of Formula I, to apatient in need thereof. The invention further provides methods oftreatment and/or prevention of depression, anxiety, psychosis,schizophrenia, psychotic disorders, bipolar disorders, cognitivedisorders, Parkinson's disease, Alzheimer's disease, attention deficithyperactivity disorder (ADHD), pain, convulsion, obesity, inflammatorydiseases including irritable bowel syndrome (IBS) and inflammatory boweldisorders, emesis, pre-eclampsia, airway related diseases includingchronic obstructive pulmonary disease, asthma, airwayhyperresponsiveness, bronchoconstriction and cough, urinaryincontinence, reproduction disorders, contraception and sexhormone-dependent diseases including but not limited to benign prostatichyperplasia (BPH), prostatic hyperplasia, metastatic prostaticcarcinoma, testicular cancer, breast cancer, ovarian cancer, androgendependent acne, male pattern baldness, endometriosis, abnormal puberty,uterine fibrosis, uterine fibroid tumor, uterine leiomyoma,hormone-dependent cancers, hyperandrogenism, hirsutism, virilization,polycystic ovary syndrome (PCOS), premenstrual dysphoric disease (PMDD),HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosisnigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia ofluteinized theca cells in ovarian stroma), other manifestations of highintraovarian androgen concentrations (e.g. follicular maturation arrest,atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding,infertility), androgen-producing tumor (virilizing ovarian or adrenaltumor), menorrhagia and adenomyosis comprising the administration of atherapeutically effective amount of a compound or pharmaceuticallyacceptable solvate of Formula I, to a patient in need thereof.Preferably the patient is a warm-blooded animal, more preferably ahuman.

The invention further provides methods of treatment for gynecologicaldisorders and infertility. In particular, the invention provides methodsto lower and/or suppress the LH-surge in assisted conception comprisingthe administration of a therapeutically effective amount of a compoundor pharmaceutically acceptable solvate of Formula I, to a patient inneed thereof. Preferably the patient is a warm-blooded animal, morepreferably a woman.

The invention further provides methods to affect androgen production tocause male castration and to inhibit the sex drive in male sexualoffenders comprising the administration of a therapeutically effectiveamount of a compound or pharmaceutically acceptable solvate of FormulaI, to a patient in need thereof. Preferably the patient is awarm-blooded animal, more preferably a man.

The invention also provides the use of a compound of Formula I or apharmaceutically acceptable solvate thereof as a medicament. Preferably,the medicament is used for the treatment and/or prevention ofdepression, anxiety, psychosis, schizophrenia, psychotic disorders,bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer'sdisease, attention deficit hyperactivity disorder (ADHD), pain,convulsion, obesity, inflammatory diseases including irritable bowelsyndrome (IBS) and inflammatory bowel disorders, emesis, pre-eclampsia,airway related diseases including chronic obstructive pulmonary disease,asthma, airway hyperresponsiveness, bronchoconstriction and cough,reproduction disorders, contraception and sex hormone-dependent diseasesincluding but not limited to benign prostatic hyperplasia (BPH),prostatic hyperplasia, metastatic prostatic carcinoma, testicularcancer, breast cancer, ovarian cancer, androgen dependent acne, malepattern baldness, endometriosis, abnormal puberty, uterine fibrosis,uterine fibroid tumor, hormone-dependent cancers, hyperandrogenism,hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrualdysphoric disease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulinresistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-ANwith hyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosis.Preferably, the medicament is used for the treatment and/or preventionof depression, anxiety, psychosis, schizophrenia, psychotic disorders,bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer'sdisease, attention deficit hyperactivity disorder (ADHD), pain,convulsion, obesity, inflammatory diseases including irritable bowelsyndrome (IBS) and inflammatory bowel disorders, emesis, pre-eclampsia,airway related diseases including chronic obstructive pulmonary disease,asthma, airway hyperresponsiveness, bronchoconstriction and cough,urinary incontinence, reproduction disorders, contraception and sexhormone-dependent diseases including but not limited to benign prostatichyperplasia (BPH), prostatic hyperplasia, metastatic prostaticcarcinoma, testicular cancer, breast cancer, ovarian cancer, androgendependent acne, male pattern baldness, endometriosis, abnormal puberty,uterine fibrosis, uterine fibroid tumor, uterine leiomyoma,hormone-dependent cancers, hyperandrogenism, hirsutism, virilization,polycystic ovary syndrome (PCOS), premenstrual dysphoric disease (PMDD),HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosisnigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia ofluteinized theca cells in ovarian stroma), other manifestations of highintraovarian androgen concentrations (e.g. follicular maturation arrest,atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding,infertility), androgen-producing tumor (virilizing ovarian or adrenaltumor), menorrhagia and adenomyosis. The medicament may also be used forthe treatment of gynecologic disorders, infertility and to affectandrogen production to cause male castration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the plasma testosterone levels over time inintact male rats after oral administration of compound no 5 (3 mg/kg) orof a vehicle (0.5% methyl cellulose).

FIG. 2 is a histogram showing the prostate weight in a rat model ofBenign Prostate Hyperplasia (BPH) after oral administration of 3, 10 or30 mg/kg of compound no 5.

FIG. 3 is a histogram showing the estradiol levels in adult, female ratstracked over the duration of consecutive estrous cycles, after oraladministration of compound no 5 (10 mg/kg) or of a vehicle (0.5% methylcellulose).

FIG. 4 is a graph showing the body temperature over time inovariectomized ewes after intravenous administration of compound no 5 (1mg/kg) or of a vehicle.

FIG. 5 is a graph showing the evolution of the primary endpoint (TT)during the course of the study as percent change from baseline (±SEM)after oral administration of compound no 5 (180 mg QD; circles) orplacebo (triangles).

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the invention relates to compounds of Formula I:

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl, nitrile or R³ is        thiophen-2-yl under the condition that R⁵ is not methyl;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl or fluoromethyl;    -   X¹ is N and X² is S or O; or X¹ is S and X² is N;    -   represents a single or a double bound depending on X¹ and X²;    -   stands for the (R)-enantiomer or for the racemate of compound of        Formula I.

In one specific embodiment of the invention, R⁵ is methyl, ethyl,methoxymethyl, trifluoromethyl, difluoromethyl, fluoromethyl,1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl. In anotherspecific embodiment, R⁵ is methyl, ethyl, methoxymethyl,trifluoromethyl, difluoromethyl or fluoromethyl. In another specificembodiment, R⁵ is 1-fluoroethyl, 1,1-difluoroethyl or2,2,2-trifluoroethyl. Preferred compounds of Formula I andpharmaceutically acceptable solvates thereof are those wherein:

-   -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl, nitrile or R³ is        thiophen-2-yl under the condition that R⁵ is not methyl;    -   R⁴ is methyl, ethyl, n-propyl or hydroxyethyl;    -   R⁵ is methyl, ethyl, trifluoromethyl, difluoromethyl,        1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl,        preferably R⁵ is methyl, ethyl or trifluoromethyl;    -   X¹ is N and X² is S or O, preferably X¹ is N and X² is S.

In an embodiment of the invention, compound of Formula I is the(R)-enantiomer. In another embodiment, compound of Formula I is theracemate.

In one embodiment, preferred compounds of Formula I are those of FormulaI′:

-   -   and pharmaceutically acceptable solvates thereof, wherein R¹,        R^(1′), R², R^(2′), R³, R⁴, R⁵, X¹ and X² are as defined in        Formula I and represents a single or a double bound depending on        X¹ and X².

In one embodiment, preferred compounds of Formula I are those of FormulaI″:

-   -   and pharmaceutically acceptable solvates thereof, wherein R¹,        R^(1′), R², R^(2′), R³, R⁴, R⁵, X¹ and X² are as defined in        Formula I and represents a single or a double bound depending on        X¹ and X².

In one embodiment, preferred compounds of Formula I are those of FormulaIa:

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl or nitrile;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl, preferably R⁴        is methyl, ethyl, n-propyl or hydroxyethyl;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably R⁵ is methyl, ethyl,        methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl,        preferably R⁵ is methyl, ethyl, trifluoromethyl or        difluoromethyl, preferably R⁵ is methyl, ethyl or        trifluoromethyl;    -   stands for the (R)-enantiomer or for the racemate of compound of        Formula Ia.

In one embodiment, preferred compounds of Formula Ia are those ofFormula Ia′ and Formula Ia″:

and pharmaceutically acceptable solvates thereof, wherein R¹, R^(1′),R², R^(2′), R³, R⁴ and R⁵ are as defined in Formula Ia. Preferredcompounds of Formula Ia′ and Ia″ and pharmaceutically acceptablesolvates thereof are those wherein:

-   -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl or nitrile;    -   R⁴ is methyl, ethyl, n-propyl or hydroxyethyl;    -   R⁵ is methyl, ethyl, trifluoromethyl or difluoromethyl,        preferably R⁵ is methyl, ethyl or trifluoromethyl.

In one embodiment, preferred compounds of Formula Ia are those ofFormula Ia-1:

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R³ is H, F, Cl, methyl, trifluoromethyl or nitrile, preferably        R³ is H, F or Cl;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl, preferably R⁴        is methyl, ethyl, n-propyl or hydroxyethyl;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably R⁵ is methyl, ethyl,        methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl,        preferably R⁵ is methyl, ethyl, trifluoromethyl or        difluoromethyl, preferably R⁵ is methyl, ethyl or        trifluoromethyl;        stands for the (R)-enantiomer or for the racemate.

In one embodiment, preferred compounds of Formula Ia-1 are those ofFormula Ia-1′:

-   -   and pharmaceutically acceptable solvates thereof, wherein R³, R⁴        and R⁵ are as defined in Formula Ia-1.

In one embodiment, preferred compounds of Formula Ia are those ofFormula Ia-2:

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl or nitrile;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably R⁵ is methyl, ethyl,        methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl,        preferably R⁵ is methyl, ethyl, trifluoromethyl or        difluoromethyl, preferably R⁵ is methyl, ethyl or        trifluoromethyl;    -   stands for the (R)-enantiomer or for the racemate.

In one embodiment, preferred compounds of Formula Ia-2 are those ofFormula Ia-2′:

and pharmaceutically acceptable solvates thereof, wherein R¹, R^(1′),R², R^(2′), R³ and R⁵ are as defined in Formula Ia-2. In one embodiment,preferred compounds of Formula Ia are those of Formula Ia-3:

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl or nitrile;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl, preferably R⁴        is methyl, ethyl, n-propyl or hydroxyethyl;    -   stands for the (R)-enantiomer or for the racemate.

In one embodiment, preferred compounds of Formula Ia-3 are those ofFormula Ia-3′:

and pharmaceutically acceptable solvates thereof, wherein R¹, R^(1′),R², R^(2′), R³ and R⁴ are as defined in Formula Ia-3. In one embodiment,preferred compounds of Formula I are those of Formula Ib:

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R³ is F or R³ is thiophen-2-yl under the condition that R⁵ is        not methyl;    -   R⁵ is methyl, ethyl, trifluoromethyl, difluoromethyl,        fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or        2,2,2-trifluoroethyl, preferably R⁵ is methyl, ethyl,        trifluoromethyl, difluoromethyl or fluoromethyl, preferably R⁵        is methyl, ethyl, 1-fluoroethyl, 1,1-difluoroethyl or        2,2,2-trifluoroethyl, preferably R⁵ is methyl or ethyl;    -   stands for the (R)-enantiomer or for the racemate of compound of        Formula Ib.

In one embodiment, preferred compounds of Formula Ib are those ofFormula Ib′:

-   -   and pharmaceutically acceptable solvates thereof, wherein R³ and        R⁵ are defined as in Formula Ib.

In one embodiment, preferred compounds of Formula Ib are those ofFormula Ib″:

-   -   and pharmaceutically acceptable solvates thereof, wherein R³ and        R⁵ are defined as in Formula Ib.

In one embodiment, preferred compounds of Formula Ib are those ofFormula Ib-1:

-   -   and pharmaceutically acceptable solvates thereof, wherein R⁵ is        methyl, ethyl, trifluoromethyl, difluoromethyl or fluoromethyl,        preferably R⁵ is methyl or ethyl.

In one embodiment, preferred compounds of Formula Ib are those ofFormula Ib-2:

-   -   and pharmaceutically acceptable solvates thereof, wherein R⁵ is        ethyl, trifluoromethyl, difluoromethyl or fluoromethyl,        preferably R⁵ is ethyl.

In one embodiment, preferred compounds of Formula I are those of FormulaIc:

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl or nitrile;    -   R⁴ is methyl, ethyl, n-propyl or hydroxyethyl;    -   R⁵ is methyl, ethyl or trifluoromethyl;    -   stands for the (R)-enantiomer or for the racemate.

In one embodiment, preferred compounds of Formula Ic are those ofFormula Ic′:

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl, preferably R¹ is H;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy, preferably R² is H;    -   R^(2′) is H or F, preferably R^(2′) is H;    -   R³ is H, F, Cl, methyl, trifluoromethyl or nitrile, preferably        R³ is F;    -   R⁴ is methyl, ethyl, n-propyl or hydroxyethyl, preferably R⁴ is        methyl;    -   R⁵ is methyl, ethyl or trifluoromethyl, preferably R⁵ is methyl.

Particularly preferred compounds of Formula I of the invention are thoselisted in Table 1 hereafter.

TABLE 1 Cpd no Structure Chemical name MW 1

(R)-(3,4-dichlorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)methanone 409.29 2

(R)-(3-(3-ethyl-1,2,4- thiadiazol-5-yl)-8-methyl- 5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone372.42 3

(R)-(4-chlorophenyl)(8- methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 374.85 4

(R)-(4-chloro-3- fluorophenyl)(8-methyl-3- (3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone392.84 5

(R)-(4-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 358.39 6

(R)-(3-chloro-4- fluorophenyl)(8-methyl-3- (3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone392.84 7

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(3,4,5-trifluorophenyl)methanone 394.37 8

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(2,3,4-trifluorophenyl)methanone 394.37 9

(R)-(3,4-difluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)methanone 376.38 10

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(2,3,4,5-tetrafluorophenyl)methanone 412.36 11

(R)-(4-fluorophenyl)(8-(2- hydroxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 388.42 12

(4-fluorophenyl)(8-(2- hydroxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 388.42 13

(R)-(3-(3-ethyl-1,2,4- oxadiazol-5-yl)-8-methyl- 5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone356.35 14

(4-fluorophenyl)(8-methyl- 3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 358.39 15

(R)-(3-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 358.39 16

(R)-(3-chlorophenyl)(8- methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 374.85 17

(R)-(3,5-difluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4] triazolo[4,3- a]pyrazin-7(8H)-yl)methanone 376.38 18

(R)-(2,4-difluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)methanone 376.38 19

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(p- tolyl)methanone354.43 20

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)(phenyl)methanone 340.421

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-(trifluoromethyl)phenyl) methanone 408.4 22

(R)-(8-ethyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 372.42 23

(8-ethyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 372.42 24

(R)-(4-fluorophenyl)(3-(3- methyl-1,2,4-thiadiazol-5-yl)-8-propyl-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)methanone 386.45 25

(R)-(4-fluoro-3- methoxyphenyl)(8-methyl- 3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)methanone 388.42 26

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(o- tolyl)methanone354.43 27

(R)-(3-methoxyphenyl)(8- methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 370.43 28

(R)-(4-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4- oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 342.33 29

(R)-4-(8-methyl-3-(3- methyl-1,2,4-thiadiazol-5- yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine-7- carbonyl)benzonitrile 365.41 30

(R)-(3-(3-ethyl-1,2,4- oxadiazol-5-yl)-8-methyl- 5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2-yl)phenyl)methanone 420.49 31

(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(2,3,4,5-tetrafluorophenyl)methanone 412.36 32

(3,4-difluorophenyl)(8- methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 376.38 33

(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(2,3,4-trifluorophenyl)methanone 394.37 34

(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(3,4,5-trifluorophenyl)methanone 394.37 35

(3-chloro-4- fluorophenyl)(8-methyl-3- (3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone392.84 36

(4-chloro-3- fluorophenyl)(8-methyl-3- (3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone392.84 37

(4-chlorophenyl)(8-methyl- 3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 374.85 38

(3,4-dichlorophenyl)(8- methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)methanone 409.29 39

(3-(3-ethyl-1,2,4-thiadiazol- 5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone372.42 40

(3-(3-ethyl-1,2,4-oxadiazol- 5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone356.35 41

(R)-(4-fluorophenyl)(8- methyl-3-(3- (trifluoromethyl)-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)methanone 412.36 42

(R)-(3-(3-(difluoromethyl)- 1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 394.37 43

(R)-(3-(3-(1,1- difluoroethyl)-1,2,4- oxadiazol-5-yl)-8-methyl-5,6-dihydro- [1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 392.34 44

(R)-(4-fluorophenyl)(8- methyl-3-(3-(2,2,2- trifluoroethyl)-1,2,4-oxadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)methanone 410.33 45

((8R)-3-(3-(1-fluoroethyl)- 1,2,4-oxadiazol-5-yl)-8- methyl-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone374.34and pharmaceutically acceptable solvates thereof.

In Table 1, the term “Cpd” means compound.

The compounds of Table 1 were named using ChemBioDraw® Ultra version12.0 (PerkinElmer).

The compounds of Formula I can be prepared by different ways withreactions known to a person skilled in the art.

The invention further relates to a process of manufacturing of compoundsof Formula I:

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl, nitrile or R³ is        thiophen-2-yl under the condition that R⁵ is not methyl;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl, preferably R⁴        is methyl, ethyl, n-propyl or hydroxyethyl;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably R⁵ is methyl, ethyl,        methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl,        preferably R⁵ is methyl, ethyl or trifluoromethyl;    -   X¹ is N and X² is S or O; or X¹ is S and X² is N, preferably X¹        is N and X² is S or O, more preferably, X¹ is N and X² is S;    -   represents a single or a double bound depending on X¹ and X²;    -   stands for the (R)-enantiomer or for the racemate of compound of        Formula I; characterized in that it comprises the following        steps:    -   a) reacting a compound of Formula (i)

-   -   wherein:    -   PG represents a suitable protecting group such as for example        DMB, PMB, Boc, allyl, diphenyl-phosphiramide (DPP),        2-trimethylsilylethanesulfonyl (SES), preferably PG is DMB;    -   R^(4′) is R⁴ as defined above or a reducible precursor of        hydroxyethyl and consequently a further precursor of        methoxyethyl, such as for example —CH₂CO₂Alkyl; where the term        “reducible precursor of hydroxyethyl or consequently a further        precursor of methoxyethyl” refers to any chemical group which,        when reacting with reducing agents, such as for example LiAlH₄,        is reduced to hydroxyethyl and then optionally further converted        to methoxyethyl;    -   stands for the (R)-enantiomer or for the racemate;        with a compound of Formula (ii)

-   -   wherein:    -   R^(5′) is R⁵ as defined above, H or        1-((tert-butyldiphenylsilyl)oxy)ethyl, preferably R^(5′) is R⁵        as defined above or H;    -   X¹ and X² are as defined above; and represents a single or a        double bound depending on X¹ and X²; so as to obtain a compound        of Formula (iii)

-   -   wherein PG, R^(4′), R^(5′), X¹ and X² are as defined above,        stands for the (R)-enantiomer or for the racemate and represents        a single or a double bound depending on X¹ and X²; b)        deprotecting compound of Formula (iii) with a suitable        deprotection agent to afford compound of Formula (iv)

-   -   -   wherein R^(4′), R^(5′), X¹ and X² are as defined above,            stands for the (R)-enantiomer or for the racemate and            represents a single or a double bound depending on X¹ and            X²;

    -   c) when R^(5′) is H, introducing a trifluoromethyl or        difluoromethyl group by direct C—H trifluoro- or        difluoromethylation, leading to compound of Formula (v)

-   -   -   wherein R^(4′), X¹ and X² are as defined above and R⁵ is            trifluoromethyl or difluoromethyl, stands for the            (R)-enantiomer or for the racemate and represents a single            or a double bound depending on X¹ and X²;

    -   d) N-acylating compound of Formula (iv) wherein R^(5′) is not H        or compound of Formula (v), with a compound of Formula (vi)

-   -   -   wherein R¹, R^(1′), R², R^(2′) and R³ are as defined above;

    -   leading to compound of Formula (vii)

-   -   -   wherein R¹, R^(1′), R², R^(2′), R³, R^(4′), X¹ and X² are as            defined above, stands for the (R)-enantiomer or for the            racemate,        -   represents a single or a double bound depending on X¹ and            X²; and R^(5″) is R⁵ as defined in Formula I or            1-((tert-butyldiphenylsilyl)oxy)ethyl;

    -   e) optionally further conducting one or both of the two        following steps:        -   e′) when R^(4′) is a reducible precursor of hydroxyethyl and            consequently a further precursor of methoxyethyl, a step of            reduction optionally followed by methyl ether formation;        -   e″) when R^(5″) is 1-((tert-butyldiphenylsilyl)oxy)ethyl, a            step of alcohol deprotection and subsequent fluorination to            form 1-fluoroethyl R⁵ group; or a step of alcohol            deprotection, followed by an oxidation step and a subsequent            fluorination step to afford 1,1-difluoroethyl R⁵ group;

    -   to afford compound of Formula I.

In a preferred embodiment, the protecting group PG used in the processof the invention is DMB.

According to one embodiment, the introduction of a trifluoromethyl ordifluoromethyl group at step c) may be performed by direct C—Htrifluoro- or difluoromethylation as described by Ji Y. et al. in PNAS,2011, 108(35), 14411-14415 or by Fujiwara Y. et al. in JACS, 2012, 134,1494-1497.

According to one embodiment, the fluorination step to form 1-fluoroethylor 1,1-difluoroethyl R⁵ groups at step e″) may be performed by DASTfluorination. DAST fluorination may be performed as described inWO2004/103953, page 51.

Reaction schemes as described in the example section are illustrativeonly and should not be construed as limiting the invention in any way.According to one embodiment, compounds of Formula I can be preparedusing the chiral synthesis of the invention detailed in the examplesbelow.

The invention is further directed to the use of the compounds of theinvention or pharmaceutically acceptable solvates thereof as antagoniststo the NK-3 receptor.

Accordingly, in a particularly preferred embodiment, the inventionrelates to the use of compounds of Formula I and subformulae inparticular those of Table 1 above, or pharmaceutically acceptablesolvates thereof, as NK-3 receptor antagonists.

Accordingly, in another aspect, the invention relates to the use ofthese compounds or solvates thereof for the synthesis of pharmaceuticalactive ingredients, such as selective NK-3 receptor antagonists.

Uses

The compounds of the invention are therefore useful as medicaments, inparticular in the prevention and/or treatment of depression, anxiety,psychosis, schizophrenia, psychotic disorders, bipolar disorders,cognitive disorders, Parkinson's disease, Alzheimer's disease, attentiondeficit hyperactivity disorder (ADHD), pain, convulsion, obesity,inflammatory diseases including irritable bowel syndrome (IBS) andinflammatory bowel disorders, emesis, pre-eclampsia, airway relateddiseases including chronic obstructive pulmonary disease, asthma, airwayhyperresponsiveness, bronchoconstriction and cough, reproductiondisorders, contraception and sex hormone-dependent diseases includingbut not limited to benign prostatic hyperplasia (BPH), prostatichyperplasia, metastatic prostatic carcinoma, testicular cancer, breastcancer, ovarian cancer, androgen dependent acne, male pattern baldness,endometriosis, abnormal puberty, uterine fibrosis, uterine fibroidtumor, hormone-dependent cancers, hyperandrogenism, hirsutism,virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoricdisease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistanceand acanthosis nigricans), ovarian hyperthecosis (HAIR-AN withhyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosis. Thecompounds of the invention are therefore useful as medicaments, inparticular in the prevention and/or treatment of depression, anxiety,psychosis, schizophrenia, psychotic disorders, bipolar disorders,cognitive disorders, Parkinson's disease, Alzheimer's disease, attentiondeficit hyperactivity disorder (ADHD), pain, convulsion, obesity,inflammatory diseases including irritable bowel syndrome (IBS) andinflammatory bowel disorders, emesis, pre-eclampsia, airway relateddiseases including chronic obstructive pulmonary disease, asthma, airwayhyperresponsiveness, bronchoconstriction and cough, urinaryincontinence, reproduction disorders, contraception and sexhormone-dependent diseases including but not limited to benign prostatichyperplasia (BPH), prostatic hyperplasia, metastatic prostaticcarcinoma, testicular cancer, breast cancer, ovarian cancer, androgendependent acne, male pattern baldness, endometriosis, abnormal puberty,uterine fibrosis, uterine fibroid tumor, uterine leiomyoma,hormone-dependent cancers, hyperandrogenism, hirsutism, virilization,polycystic ovary syndrome (PCOS), premenstrual dysphoric disease (PMDD),HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosisnigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia ofluteinized theca cells in ovarian stroma), other manifestations of highintraovarian androgen concentrations (e.g. follicular maturation arrest,atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding,infertility), androgen-producing tumor (virilizing ovarian or adrenaltumor), menorrhagia and adenomyosis.

The invention also provides for a method for delaying in patient theonset of depression, anxiety, psychosis, schizophrenia, psychoticdisorders, bipolar disorders, cognitive disorders, Parkinson's disease,Alzheimer's disease, attention deficit hyperactivity disorder (ADHD),pain, convulsion, obesity, inflammatory diseases including irritablebowel syndrome (IBS) and inflammatory bowel disorders, emesis,pre-eclampsia, airway related diseases including chronic obstructivepulmonary disease, asthma, airway hyperresponsiveness,bronchoconstriction and cough, reproduction disorders, contraception andsex hormone-dependent diseases including but not limited to benignprostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostaticcarcinoma, testicular cancer, breast cancer, ovarian cancer, androgendependent acne, male pattern baldness, endometriosis, abnormal puberty,uterine fibrosis, uterine fibroid tumor, hormone-dependent cancers,hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome(PCOS), premenstrual dysphoric disease (PMDD), HAIR-AN syndrome(hyperandrogenism, insulin resistance and acanthosis nigricans), ovarianhyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells inovarian stroma), other manifestations of high intraovarian androgenconcentrations (e.g. follicular maturation arrest, atresia, anovulation,dysmenorrhea, dysfunctional uterine bleeding, infertility),androgen-producing tumor (virilizing ovarian or adrenal tumor),menorrhagia and adenomyosis comprising the administration of apharmaceutically effective amount of a compound of Formula I orpharmaceutically acceptable solvate thereof to a patient in needthereof. The invention also provides for a method for delaying inpatient the onset of depression, anxiety, psychosis, schizophrenia,psychotic disorders, bipolar disorders, cognitive disorders, Parkinson'sdisease, Alzheimer's disease, attention deficit hyperactivity disorder(ADHD), pain, convulsion, obesity, inflammatory diseases includingirritable bowel syndrome (IBS) and inflammatory bowel disorders, emesis,pre-eclampsia, airway related diseases including chronic obstructivepulmonary disease, asthma, airway hyperresponsiveness,bronchoconstriction and cough, urinary incontinence, reproductiondisorders, contraception and sex hormone-dependent diseases includingbut not limited to benign prostatic hyperplasia (BPH), prostatichyperplasia, metastatic prostatic carcinoma, testicular cancer, breastcancer, ovarian cancer, androgen dependent acne, male pattern baldness,endometriosis, abnormal puberty, uterine fibrosis, uterine fibroidtumor, uterine leiomyoma, hormone-dependent cancers, hyperandrogenism,hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrualdysphoric disease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulinresistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-ANwith hyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosiscomprising the administration of a pharmaceutically effective amount ofa compound of Formula I or pharmaceutically acceptable solvate thereofto a patient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

The compounds of the invention are especially useful in the treatmentand/or prevention of sex hormone-dependent diseases including but notlimited to benign prostatic hyperplasia (BPH), prostatic hyperplasia,metastatic prostatic carcinoma, testicular cancer, breast cancer,ovarian cancer, androgen dependent acne, male pattern baldness,endometriosis, abnormal puberty, uterine fibrosis, uterine fibroidtumor, hormone-dependent cancers, hyperandrogenism, hirsutism,virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoricdisease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistanceand acanthosis nigricans), ovarian hyperthecosis (HAIR-AN withhyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosis. Thecompounds of the invention are especially useful in the treatment and/orprevention of sex hormone-dependent diseases including but not limitedto benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastaticprostatic carcinoma, testicular cancer, breast cancer, ovarian cancer,androgen dependent acne, male pattern baldness, endometriosis, abnormalpuberty, uterine fibrosis, uterine fibroid tumor, uterine leiomyoma,hormone-dependent cancers, hyperandrogenism, hirsutism, virilization,polycystic ovary syndrome (PCOS), premenstrual dysphoric disease (PMDD),HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosisnigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia ofluteinized theca cells in ovarian stroma), other manifestations of highintraovarian androgen concentrations (e.g. follicular maturation arrest,atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding,infertility), androgen-producing tumor (virilizing ovarian or adrenaltumor), menorrhagia and adenomyosis.

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of benign prostatichyperplasia (BPH), endometriosis, uterine fibrosis, uterine fibroidtumor, polycystic ovary syndrome (PCOS), premenstrual dysphoric disease(PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistance andacanthosis nigricans), ovarian hyperthecosis (HAIR-AN with hyperplasiaof luteinized theca cells in ovarian stroma), other manifestations ofhigh intraovarian androgen concentrations (e.g. follicular maturationarrest, atresia, anovulation, dysmenorrhea, dysfunctional uterinebleeding, infertility), androgen-producing tumor (virilizing ovarian oradrenal tumor), menorrhagia and adenomyosis. In a specific embodiment,the compounds of the invention are especially useful in the treatmentand/or prevention of benign prostatic hyperplasia (BPH), endometriosis,uterine fibrosis, uterine fibroid tumor, uterine leiomyoma, polycysticovary syndrome (PCOS), premenstrual dysphoric disease (PMDD), HAIR-ANsyndrome (hyperandrogenism, insulin resistance and acanthosisnigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia ofluteinized theca cells in ovarian stroma), other manifestations of highintraovarian androgen concentrations (e.g. follicular maturation arrest,atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding,infertility), androgen-producing tumor (virilizing ovarian or adrenaltumor), menorrhagia and adenomyosis.

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of endometriosis, uterinefibrosis, uterine fibroid tumor, uterine leiomyoma, polycystic ovarysyndrome (PCOS) and benign prostatic hyperplasia (BPH).

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of endometriosis.

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of uterine fibrosis.

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of uterine fibroid tumor.

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of uterine leiomyoma.

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of polycystic ovary syndrome(PCOS).

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of benign prostatichyperplasia (BPH).

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of hot flashes also known ashot flushes.

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of peri-menopausal conditions(i.e. ‘hot flashes’), in vitro fertilization (‘IVF’), malecontraceptive, female contraceptive, castration of sex offenders.

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of hot flashes related toperi-menopausal conditions, menopausal conditions and/or postmenopausalconditions.

In a specific embodiment, the compounds of the invention are especiallyuseful in the treatment and/or prevention of hot flashes which are aconsequence of hormone therapy intentionally lowering the level of sexhormones, such as for example therapy-induced hot flashes in breast,uterine or prostate cancers.

The compounds of the invention are also useful in the treatment ofgynecological disorders and infertility. In particular, the inventionprovides methods to lower and/or suppress the LH-surge in assistedconception.

The compounds of the invention are also useful to cause male castrationand to inhibit the sex drive in men. This is of particular interest inthe treatment of male sexual offenders.

The invention further provides the use of a compound of Formula I or apharmaceutically acceptable solvate thereof for the manufacture of amedicament for treating and/or preventing depression, anxiety,psychosis, schizophrenia, psychotic disorders, bipolar disorders,cognitive disorders, Parkinson's disease, Alzheimer's disease, attentiondeficit hyperactivity disorder (ADHD), pain, convulsion, obesity,inflammatory diseases including irritable bowel syndrome (IBS) andinflammatory bowel disorders, emesis, pre-eclampsia, airway relateddiseases including chronic obstructive pulmonary disease, asthma, airwayhyperresponsiveness, bronchoconstriction and cough, reproductiondisorders, contraception and sex hormone-dependent diseases includingbut not limited to benign prostatic hyperplasia (BPH), prostatichyperplasia, metastatic prostatic carcinoma, testicular cancer, breastcancer, ovarian cancer, androgen dependent acne, male pattern baldness,endometriosis, abnormal puberty, uterine fibrosis, uterine fibroidtumor, hormone-dependent cancers, hyperandrogenism, hirsutism,virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoricdisease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistanceand acanthosis nigricans), ovarian hyperthecosis (HAIR-AN withhyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosis in apatient. The invention further provides the use of a compound of FormulaI or a pharmaceutically acceptable solvate thereof for the manufactureof a medicament for treating and/or preventing depression, anxiety,psychosis, schizophrenia, psychotic disorders, bipolar disorders,cognitive disorders, Parkinson's disease, Alzheimer's disease, attentiondeficit hyperactivity disorder (ADHD), pain, convulsion, obesity,inflammatory diseases including irritable bowel syndrome (IBS) andinflammatory bowel disorders, emesis, pre-eclampsia, airway relateddiseases including chronic obstructive pulmonary disease, asthma, airwayhyperresponsiveness, bronchoconstriction and cough, urinaryincontinence, reproduction disorders, contraception and sexhormone-dependent diseases including but not limited to benign prostatichyperplasia (BPH), prostatic hyperplasia, metastatic prostaticcarcinoma, testicular cancer, breast cancer, ovarian cancer, androgendependent acne, male pattern baldness, endometriosis, abnormal puberty,uterine fibrosis, uterine fibroid tumor, uterine leiomyoma,hormone-dependent cancers, hyperandrogenism, hirsutism, virilization,polycystic ovary syndrome (PCOS), premenstrual dysphoric disease (PMDD),HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosisnigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia ofluteinized theca cells in ovarian stroma), other manifestations of highintraovarian androgen concentrations (e.g. follicular maturation arrest,atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding,infertility), androgen-producing tumor (virilizing ovarian or adrenaltumor), menorrhagia and adenomyosis in a patient.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

The invention especially provides the use of a compound of Formula I ora pharmaceutically acceptable solvate thereof for the manufacture of amedicament to treat and/or prevent sex hormone-dependent diseasesincluding but not limited to benign prostatic hyperplasia (BPH),prostatic hyperplasia, metastatic prostatic carcinoma, testicularcancer, breast cancer, ovarian cancer, androgen dependent acne, malepattern baldness, endometriosis, abnormal puberty, uterine fibrosis,uterine fibroid tumor, hormone-dependent cancers, hyperandrogenism,hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrualdysphoric disease (PMDD), HAIR-AN syndrome (hyperandrogenism, insulinresistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-ANwith hyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility), androgen-producing tumor(virilizing ovarian or adrenal tumor), menorrhagia and adenomyosis. Theinvention especially provides the use of a compound of Formula I or apharmaceutically acceptable solvate thereof for the manufacture of amedicament to treat and/or prevent sex hormone-dependent diseasesincluding but not limited to benign prostatic hyperplasia (BPH),prostatic hyperplasia, metastatic prostatic carcinoma, testicularcancer, breast cancer, ovarian cancer, androgen dependent acne, malepattern baldness, endometriosis, abnormal puberty, uterine fibrosis,uterine fibroid tumor, uterine leiomyoma, hormone-dependent cancers,hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome(PCOS), premenstrual dysphoric disease (PMDD), HAIR-AN syndrome(hyperandrogenism, insulin resistance and acanthosis nigricans), ovarianhyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells inovarian stroma), other manifestations of high intraovarian androgenconcentrations (e.g. follicular maturation arrest, atresia, anovulation,dysmenorrhea, dysfunctional uterine bleeding, infertility),androgen-producing tumor (virilizing ovarian or adrenal tumor),menorrhagia and adenomyosis.

In a specific embodiment, compounds of Formula I or a pharmaceuticallyacceptable solvate thereof may be used for the manufacture of amedicament to treat and/or prevent endometriosis, uterine fibrosis,uterine fibroid tumor, uterine leiomyoma, polycystic ovary syndrome(PCOS) and benign prostatic hyperplasia (BPH).

In a specific embodiment, compounds of Formula I or a pharmaceuticallyacceptable solvate thereof may be used for the manufacture of amedicament to treat and/or prevent endometriosis.

In a specific embodiment, compounds of Formula I or a pharmaceuticallyacceptable solvate thereof may be used for the manufacture of amedicament to treat and/or prevent uterine fibrosis.

In a specific embodiment, compounds of Formula I or a pharmaceuticallyacceptable solvate thereof may be used for the manufacture of amedicament to treat and/or prevent uterine fibroid tumor.

In a specific embodiment, compounds of Formula I or a pharmaceuticallyacceptable solvate thereof may be used for the manufacture of amedicament to treat and/or prevent uterine leiomyoma.

In a specific embodiment, compounds of Formula I or a pharmaceuticallyacceptable solvate thereof may be used for the manufacture of amedicament to treat and/or prevent polycystic ovary syndrome (PCOS).

In a specific embodiment, compounds of Formula I or a pharmaceuticallyacceptable solvate thereof may be used for the manufacture of amedicament to treat and/or prevent benign prostatic hyperplasia (BPH).

In a specific embodiment, compounds of Formula I or a pharmaceuticallyacceptable solvate thereof may be used for the manufacture of amedicament to treat and/or prevent hot flashes also known as hotflushes.

The invention further provides the use of a compound of Formula I or apharmaceutically acceptable solvate thereof for the manufacture of amedicament to lower and/or suppress the LH-surge in assisted conceptionin a patient. Preferably the patient is a warm-blooded animal, morepreferably a woman.

The invention further provides the use of a compound of Formula I or apharmaceutically acceptable solvate thereof for the manufacture of amedicament to cause male castration and to inhibit the sex drive in men.This is of particular interest in the treatment of male sexualoffenders.

According to a further feature of the present invention there isprovided a method for modulating NK-3 receptor activity, in a patient,preferably a warm blooded animal, and even more preferably a human, inneed of such treatment, which comprises administering to said patient aneffective amount of compound of the present invention, or apharmaceutically acceptable solvate thereof.

According to one embodiment, the compounds of the invention, theirpharmaceutical acceptable solvates may be administered as part of acombination therapy. Thus, are included within the scope of the presentinvention embodiments comprising coadministration of, and compositionsand medicaments which contain, in addition to a compound of the presentinvention, a pharmaceutically acceptable solvate thereof as activeingredient, additional therapeutic agents and/or active ingredients.Such multiple drug regimens, often referred to as “combination therapy”,may be used in the treatment and/or prevention of any of the diseases orconditions mediated by or associated with NK-3 receptor modulation. Theuse of such combinations of therapeutic agents is especially pertinentwith respect to the treatment of the above-mentioned disorders within apatient in need of treatment or one at risk of becoming such a patient.

In addition to the requirement of therapeutic efficacy, which maynecessitate the use of active agents in addition to the NK-3 receptormodulator compounds of Formula I or pharmaceutical acceptable solvatesthereof, there may be additional rationales which compel or highlyrecommend the use of combinations of drugs involving active ingredientswhich represent adjunct therapy, i.e., which complement and supplementthe function performed by the NK-3 receptor modulator compounds of thepresent invention. Suitable supplementary therapeutic agents used forthe purpose of auxiliary treatment include drugs which, instead ofdirectly treating or preventing a disease or condition mediated by orassociated with NK-3 receptor modulation, treat diseases or conditionswhich directly result from or indirectly accompany the basic orunderlying NK-3 receptor modulated disease or condition.

According to a further feature of the present invention, the compound ofFormula I, a pharmaceutically acceptable solvate thereof may be used incombination therapy with antipsychotic drugs (APD), to improve theefficacy and to minimize secondary effects associated to APD includingbut not limited to Dopamine 2/3 and 5-HT2 receptors antagonists. Moreparticular the compound of Formula I, a pharmaceutically acceptablesolvate thereof may be used as an adjunct therapy in combination with anatypical antipsychotic drug, including but not limited to risperidone,clozapine, olanzapine, where the NK-3 receptor modulator may serve arole as dose-limiting for the atypical antipsychotic and therefore sparethe patient from some of the side effect of those atypical antipsychoticdrugs.

Thus, the methods of treatment and pharmaceutical compositions of thepresent invention may employ the compounds of Formula I orpharmaceutical acceptable solvates thereof in the form of monotherapy,but said methods and compositions may also be used in the form ofmultiple therapy in which one or more compounds of Formula I or theirpharmaceutically acceptable solvates are coadministered in combinationwith one or more other therapeutic agents.

In the above-described embodiment combinations of the present invention,the compound of Formula I, a pharmaceutically acceptable solvate thereofand other therapeutic active agents may be administered in terms ofdosage forms either separately or in conjunction with each other, and interms of their time of administration, either serially orsimultaneously. Thus, the administration of one component agent may beprior to, concurrent with, or subsequent to the administration of theother component agent(s).

The invention also provides pharmaceutical compositions comprising acompound of Formula I or a pharmaceutically acceptable solvate thereofand at least one pharmaceutically acceptable carrier, diluent, excipientand/or adjuvant. As indicated above, the invention also coverspharmaceutical compositions which contain, in addition to a compound ofthe present invention, a pharmaceutically acceptable solvate thereof asactive ingredient, additional therapeutic agents and/or activeingredients.

Another object of this invention is a medicament comprising at least onecompound of the invention, or a pharmaceutically acceptable solvatethereof, as active ingredient.

According to a further feature of the present invention there isprovided the use of a compound of Formula I or a pharmaceuticallyacceptable solvate thereof for the manufacture of a medicament formodulating NK-3 receptor activity in a patient, in need of suchtreatment, which comprises administering to said patient an effectiveamount of compound of the present invention, or a pharmaceuticallyacceptable solvate thereof.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

As set forth above, the compounds of the invention, theirpharmaceutically acceptable solvates may be used in monotherapy or incombination therapy. Thus, according to one embodiment, the inventionprovides the use of a compound of the invention for the manufacture of amedicament for at least one of the purposes described above, whereinsaid medicament is administered to a patient in need thereof, preferablya warm-blooded animal, and even more preferably a human, in combinationwith at least one additional therapeutic agent and/or active ingredient.The benefits and advantages of such a multiple drug regimen, possibleadministration regimens as well as suitable additional therapeuticagents and/or active ingredients are those described above.

Generally, for pharmaceutical use, the compounds of the invention may beformulated as a pharmaceutical preparation comprising at least onecompound of the invention and at least one pharmaceutically acceptablecarrier, diluent, excipient and/or adjuvant, and optionally one or morefurther pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a formsuitable for oral administration, for parenteral administration (such asby intravenous, intramuscular or subcutaneous injection or intravenousinfusion), for topical administration (including ocular), foradministration by inhalation, by a skin patch, by an implant, by asuppository, etc. Such suitable administration forms—which may be solid,semi-solid or liquid, depending on the manner of administration—as wellas methods and carriers, diluents and excipients for use in thepreparation thereof, will be clear to the skilled person; reference ismade to the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations includetablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes,lotions, soft and hard gelatin capsules, suppositories, drops, sterileinjectable solutions and sterile packaged powders (which are usuallyreconstituted prior to use) for administration as a bolus and/or forcontinuous administration, which may be formulated with carriers,excipients, and diluents that are suitable per se for such formulations,such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose, (sterile) water, methylcellulose, methyl- andpropylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetableoils and mineral oils or suitable mixtures thereof. The formulations canoptionally contain other substances that are commonly used inpharmaceutical formulations, such as lubricating agents, wetting agents,emulsifying and suspending agents, dispersing agents, desintegrants,bulking agents, fillers, preserving agents, sweetening agents, flavoringagents, flow regulators, release agents, etc. The compositions may alsobe formulated so as to provide rapid, sustained or delayed release ofthe active compound(s) contained therein.

The pharmaceutical preparations of the invention are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use. Generally, such unit dosageswill contain between 0.05 and 1000 mg, and usually between 1 and 500 mg,preferably between 2 and 150 mg of at least one compound of theinvention, e.g. about 2, 4, 8, 16, 32, 64 or 128 mg per unit dosage.According to another embodiment, such unit dosages will contain between0.05 and 1000 mg, and usually between 1 and 500 mg, preferably between 2and 400 mg, preferably between 2 and 200 mg of at least one compound ofthe invention per unit dosage.

Usually, depending on the condition to be prevented or treated and theroute of administration, the active compound of the invention willusually be administered between 0.001 and 10 mg per kilogram bodyweight, more often between 0.01 and 4 mg per kilogram body weight,preferably between 0.02 and 1.5 mg per kilogram body weight, for exampleabout 0.02, 0.04, 0.08, 0.16, 0.32, 0.64 or 1.28 mg, per kilogram bodyweight of the patient per day, which may be administered as a singledaily dose, divided over one or more daily doses, or essentiallycontinuously, e.g. using a drip infusion. According to anotherembodiment, the active compound of the invention will usually beadministered between 0.001 and 10 mg per kilogram body weight, moreoften between 0.01 and 7 mg per kilogram body weight, preferably between0.03 and 3.5 mg per kilogram body weight of the patient per day, whichmay be administered as a single daily dose, divided over one or moredaily doses, or essentially continuously, e.g. using a drip infusion.

According to one embodiment, the active compound of the invention willbe administered as a single daily dose, divided over one, two or moredaily doses, or essentially continuously, e.g. using a drip infusion.

Definitions

The definitions and explanations below are for the terms as usedthroughout the entire application, including both the specification andthe claims.

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless indicatedotherwise.

The term “alkyl” refers to a hydrocarbyl radical of formulaC_(n)H_(2n+1) wherein n is a number greater than or equal to 1.Generally, alkyl groups of this invention comprise from 1 to 4 carbonatoms, preferably from 1 to 3 carbon atoms. Alkyl groups may be linearor branched. Suitable alkyl groups include but are not limited tomethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl andt-butyl.

The term “thiophen-2-yl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The ring atoms of(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazinesof the invention are numbered based on scheme below.

Bonds from an asymmetric carbon in compounds are generally depictedusing a solid line (-), a solid wedge

or a dotted wedge

The use of either a solid or dotted wedge to depict bonds from anasymmetric carbon atom is meant to indicate that only the stereoisomershown is meant to be included.

The compounds of Formula I and subformulae thereof contain a stereogeniccarbon center at position 8 and thus may exist as (R)- and(S)-enantiomers. In an embodiment of the invention, compounds of FormulaI are not pure (S)-enantiomers relative to the C8 position.

In the compounds of the invention, a dotted wedge

carrying a substituent at the C8 position is used to depict the(R)-enantiomer, thus excluding racemic mixtures thereof.

In the compounds of the invention, a dotted line with a star next to theC8 position (

) is used to depict either a dotted wedge

to represent the (R)-enantiomer or a solid line (-) to depict theracemic mixture of (R)- and (S)-enantiomer, which is called “racemate”.

For instance,(R)-(3,4-dichlorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone(compound no 1) is depicted as:

The racemic mixture of this compound,(3,4-dichlorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone(compound no 38) is depicted as:

The term “solvate” is used herein to describe a compound in thisinvention that contains stoichiometric or sub-stoichiometric amounts ofone or more pharmaceutically acceptable solvent molecule such asethanol. The term “hydrate” refers to when the said solvent is water.

All references to compounds of Formula I include references to solvates,multi-component complexes and liquid crystals thereof.

The compounds of the invention include compounds of Formula I ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and prodrugs thereof and isotopically-labeledcompounds of Formula I.

The invention also generally covers all pharmaceutically acceptablepredrugs and prodrugs of the compounds of Formula I.

The term “prodrug” as used herein means the pharmacologically acceptablederivatives of compounds of Formula I, such as for example esters, whosein vivo biotransformation product generates the biologically activedrug. Prodrugs are generally characterized by increased bio-availabilityand are readily metabolized into biologically active compounds in vivo.

The term “predrug”, as used herein, means any compound that will bemodified to form a drug species, wherein the modification may take placeeither inside or outside of the body, and either before or after thepredrug reaches the area of the body where administration of the drug isindicated.

The term “patient” refers to a warm-blooded animal, more preferably ahuman, who/which is awaiting the receipt of, or is receiving medicalcare or is/will be the object of a medical procedure.

The term “human” refers to a subject of both genders and at any stage ofdevelopment (i.e. neonate, infant, juvenile, adolescent, adult).

The terms “treat”, “treating” and “treatment, as used herein, are meantto include alleviating, attenuating or abrogating a condition or diseaseand/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention”, as used herein,refer to a method of delaying or precluding the onset of a condition ordisease and/or its attendant symptoms, barring a patient from acquiringa condition or disease, or reducing a patient's risk of acquiring acondition or disease.

The term “therapeutically effective amount” (or more simply an“effective amount”) as used herein means the amount of active agent oractive ingredient (e.g. NK-3 antagonist) that is sufficient to achievethe desired therapeutic or prophylactic effect in the patient towhich/whom it is administered.

The term “administration”, or a variant thereof (e.g. “administering”),means providing the active agent or active ingredient (e.g. a NK-3antagonist), alone or as part of a pharmaceutically acceptablecomposition, to the patient in whom/which the condition, symptom, ordisease is to be treated or prevented.

By “pharmaceutically acceptable” is meant that the ingredients of apharmaceutical composition are compatible with each other and notdeleterious to the patient thereof.

The term “antagonist” as used herein means a compound that competitivelyor non-competitively binds to a receptor at the same site as an agonist(for example, the endogenous ligand) and has reversible and competitivebinding affinity to a receptor without direct modulation of receptorsignaling, but that nonetheless occupies the binding site of an agonist(for example, the endogenous ligand) to thereby block agonist-mediatedreceptor signaling.

The term “sex hormone-dependent disease” as used herein means a diseasewhich is exacerbated by, or caused by, excessive, inappropriate orunregulated sex hormone production and/or an extraordinary physiologicalresponse to sex hormones. Examples of such diseases in men include butare not limited to benign prostatic hyperplasia (BPH), prostatichyperplasia, metastatic prostatic carcinoma, testicular cancer, androgendependent acne, male pattern baldness and precocious puberty in boys.Examples of such diseases in women include but are not limited toendometriosis, abnormal puberty, uterine fibrosis, uterine fibroidtumor, uterine leiomyoma, hormone-dependent cancers (ovarian cancer,breast cancer), androgen-producing tumor (virilizing ovarian or adrenaltumor), hyperandrogenism, hirsutism, virilization, polycystic ovarysyndrome (PCOS), premenstrual dysphoric disease (PMDD), HAIR-AN syndrome(hyperandrogenism, insulin resistance and acanthosis nigricans), ovarianhyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells inovarian stroma), other manifestations of high intraovarian androgenconcentrations (e.g. follicular maturation arrest, atresia, anovulation,dysmenorrhea, dysfunctional uterine bleeding, infertility), menorrhagiaand adenomyosis (abnormal endometrial growth within the muscle of theuterus).

The term “Psychotic disorders” as used herein means a group of illnessesthat affect the mind. These illnesses alter a patient's ability to thinkclearly, make good judgments, respond emotionally, communicateeffectively, understand reality, and behave appropriately. When symptomsare severe, patient with psychotic disorders have difficulty staying intouch with reality and are often unable to meet the ordinary demands ofdaily life. Psychotic disorders include but are not limited to,schizophrenia, schizophreniform disorder, schizo-affective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition,substance-induced psychotic disorder or psychotic disorders nototherwise specified (Diagnostic and Statistical Manual of MentalDisorders, Ed. 4th, American Psychiatric Association, Washington, D.C.1994).

The term “pharmaceutical vehicle” as used herein means a carrier orinert medium used as solvent or diluent in which the pharmaceuticallyactive agent is formulated and/or administered. Non-limiting examples ofpharmaceutical vehicles include creams, gels, lotions, solutions, andliposomes.

The present invention will be better understood with reference to thefollowing examples. These examples are intended to representative ofspecific embodiments of the invention, and are not intended as limitingthe scope of the invention.

EXAMPLES Chemistry Examples

All reported temperatures are expressed in degrees Celsius (° C.); allreactions were carried out at room temperature (RT) unless otherwisestated.

All reactions were followed by thin layer chromatography (TLC) analysis(TLC plates, silica gel 60 F₂₅₄, Merck) was used to monitor reactions,establish silica-gel flash chromatography conditions. All other TLCdeveloping agents/visualization techniques, experimental set-up orpurification procedures that were used in this invention, when notdescribed in specific details, are assumed to be known to thoseconversant in the art and are described in such standard referencemanuals as: i) Gordon, A. J.; Ford, R. A. “The Chemist's Companion—AHandbook of Practical Data, Techniques, and References”, Wiley: NewYork, 1972; ii) Vogel's Textbook of Practical Organic Chemistry, PearsonPrentice Hall: London, 1989.

HPLC-MS spectra were typically obtained on an Agilent LCMS usingelectrospray ionization (ESI). The Agilent instrument includes anautosampler 1100, a binary pump 1100, an ultraviolet multi-wavelengthdetector 1100 and a 6100 single-quad mass-spectrometer. Thechromatography column used was Sunfire 3.5 μm, C18, 3.0×50 mm indimensions.

Eluent typically used was a mixture of solution A (0.1% TFA in H₂O) andsolution B (0.1% TFA in MeCN).

Gradient was applied at a flow rate of 1.3 mL per minute as follows:gradient A (for analysis of final compounds and intermediates): held theinitial conditions of 5% solution B for 0.2 min, increased linearly to95% solution B in 6 min, held at 95% during 1.75 min, returned toinitial conditions in 0.25 min and maintained for 2.0 min; gradient B(for analysis of crude samples and reactions mixtures): held the initialconditions of 5% solution B for 0.2 min, increased linearly to 95% in2.0 min, held at 95% during 1.75 min, returned to initial conditions in0.25 min and maintained for 2 min.

Determination of chiral purity was made using chiral HPLC that wasperformed on an Agilent 1100 (binary pump and a ultraviolet multiwavelength detector) with manual or automatic (Autosampler 1100)injection capabilities. Column used is CHIRALPAK IA 5 μm, 4.6×250 mm4.6×250 mm in isocratic mode. Choice of eluent was predicated on thespecifics of each separation. Further details concerning the chiral HPLCmethods used are provided below.

Method A: column CHIRALPAK IA 5 μm, 4.6×250 mm, eluent: EtOAc plus 0.1%of DEA, flow rate: 1.0 mL per minute; UV detection at 254 or 280 nm;column at RT, eluent was used as sample solvent.

Method B: column CHIRALPAK IA 5 μm, 4.6×250 mm, eluent: EtOAc/hexane(50:50) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detection at254 or 280 nm; column at RT, eluent was used as sample solvent.

Method C: column CHIRALPAK IA 5 μm 4.6×250 mm, eluent: hexane/ethanol(80:20 v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detectionat 254 or 280 nm, column at RT, eluent was used as sample solvent.

Method D: column CHIRALPAK IA 5 μm 4.6×250 mm, eluent: hexane/ethanol(50:50 v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detectionat 254 or 280 nm, column at RT, eluent was used as sample solvent.

Method E: column CHIRALPAK ID 5 μm 4.6×250 mm, eluent: hexane/ethanol(80:20 v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detectionat 254 or 280 nm, column at RT, eluent was used as sample solvent.

Method F: column CHIRALPAK IA 5 μm 4.6×250 mm, eluent: DCM/ethanol (98:2v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detection at 254or 280 nm, column at RT, eluent was used as sample solvent.

Method G: column CHIRALPAK IA 5 μm 4.6×250 mm, eluent: DCM/ethanol (98:2v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detection at 254or 280 nm, column at RT, eluent was used as sample solvent.

Method H: column CHIRALPAK IB 5 μm 4.6×250 mm, eluent: TBME plus 0.1% ofDEA, flow rate: 1.0 mL per minute; UV detection at 254 or 280 nm, columnat RT, eluent was used as sample solvent.

Method I: column CHIRALPAK IC 5 μm 4.6×250 mm, eluent: TBME/ethanol(98:2 v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detectionat 254 or 280 nm, column at RT, eluent was used as sample solvent.

Method J: column CHIRALPAK ID 5 μm 4.6×250 mm, eluent: EtOAc/DCM/IPAethanol (3:1:1 v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UVdetection at 254 or 280 nm, column at RT, eluent was used as samplesolvent.

Method K: column CHIRALPAK IC 5 μm 4.6×250 mm, eluent: TBME/methanol(98:2 v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detectionat 254 or 280 nm, column at RT, eluent was used as sample solvent.

Method L: column CHIRALPAK IB 5 μm 4.6×250 mm, eluent: TBME/methanol(98:2 v/v) plus 0.1% of DEA, flow rate: 1.0 mL per minute; UV detectionat 254 or 280 nm, column at RT, eluent was used as sample solvent.

Preparative HPLC purifications were typically carried out on an Agilent1200 instrument (preparative pump 1200 and ultraviolet multi wavelengthdetector 1200) with manual injection. The chromatography column used wasWaters Sunfire 5 μm, C18, 19×100 mm, or XBridge 5 μm, C18, 19×100 mmdepending on the type of eluent system employed, i.e. low pH or high pHconditions.

For high-pH HPLC purifications, eluent typically consisted of a mixtureof solution A (0.04 M ammonium bicarbonate in H₂O plus 0.1% of conc.NH₄OH) and solution B was MeCN. The gradient was adapted depending onthe impurity profile in each sample purified, thereby allowingsufficient separation between the impurities and the desired compound.

In rare cases when high-pH HPLC purification did not provide sufficientpurity, low-pH HPLC was applied. For low-pH HPLC purifications, eluenttypically consisted of a mixture of solution A (0.1% of TFA in H₂O) andsolution B was MeCN. The gradient was adapted depending on the impurityprofile in each sample purified, thereby allowing sufficient separationbetween the impurities and the desired compound. TFA was removed fromevaporated fractions by liquid-liquid extraction.

Chiral preparative HPLC purifications were performed on an Agilent 1200instrument (preparative pump 1200 and ultraviolet multi wavelengthdetector 1200) with manual injection. The chiral columns used areCHIRALPAK IA 5 μm, 20×250 mm or CHIRALPAK IA 5 μm, 10×250 mm. All chiralHPLC methods were employed in an isocratic mode. The eluent mixture wasselected based on the analytical chiral HPLC experiment (see above) thatprovided the best chiral separation.

¹H (300 MHz), ¹⁹F (282 MHz) and ¹³C NMR (75 MHz) spectra were recordedon a Bruker Avance DRX 300 instrument. Chemical shifts are expressed inparts per million, (ppm, δ units). Coupling constants are expressed inHertz (Hz). Abbreviations for multiplicities observed in NMR spectra areas follows: s (singlet), d (doublet), t (triplet), q (quadruplet), m(multiplet), br (broad).

Solvents, reagents and starting materials were purchased and used asreceived from commercial vendors unless otherwise specified.

The following abbreviations are used:

-   -   Boc: tert-Butoxycarbonyl,    -   Cpd: Compound,    -   DAST: (Diethylamino)sulfur trifluoride,    -   DCM: Dichloromethane,    -   DEA: Diethylamine,    -   DMB: 2,4-Dimethoxybenzyl,    -   DMB-CHO: 2,4-Dimethoxybenzaldehyde,    -   DPP: Diphenylphosphiramide,    -   ee: Enantiomeric excess,    -   eq.: Equivalent(s),    -   EtOAc: Ethyl acetate,    -   EtOH: Ethanol,    -   g: Gram(s),    -   h: Hour(s),    -   IPA: iso-Propylalcohol,    -   L: Liter(s),    -   MeOH: Methanol,    -   μL: Microliter(s),    -   mg: Milligram(s),    -   mL: Milliliter(s),    -   mmol: Millimole(s),    -   min: Minute(s),    -   P: UV purity at 254 nm or 215 nm determined by HPLC-MS,    -   PMB: 4-Methoxybenzyl,    -   rt: Room temperature,    -   SES: 2-Trimethylsilylethanesulfonyl,    -   tBu: tert-Butyl,    -   TBDPS: tert-Butyldiphenylsilyl,    -   TBME: tert-Butyl methyl ether,    -   TFA: Trifluoroacetic acid,    -   TLC: Thin layer chromatography.

The intermediates and compounds described below were named usingChemBioDraw® Ultra version 12.0 (PerkinElmer).

I. Racemic Synthesis I.1. General Synthetic Scheme for Racemic Synthesis

Compounds of the invention may be synthesized using the methodologydescribed in Scheme 1, which represents the racemic product synthesis.The racemic products may then be subjected to chiral HPLC for chiralseparation.

The general synthetic scheme comprises the following steps:

Step 1: DMB-protected ketopiperazine 1.1 was converted to iminoether 1by using the Meerwein reagent (Et₃OBF₄).

Step 2: Ester 2.2 was subsequently converted to acyl hydrazide 2. Ester2.2 may be obtained be esterification of acid 2.1.

Step 3: Cyclodehydration between the acyl hydrazide 2 and the iminoether1 furnished the protected triazolopiperazine 3.1. Thereafter, 3.1 wassubjected to acidolytic deprotection to obtain 3. When applicable, R⁵was introduced from R^(5′) affording 3′.

Step 4: The thus obtained triazolopiperazine intermediate 3 (or 3′) wasacylated through reaction with the appropriate acid chloride 4.1 toobtain the racemic final target structure represented by the generalFormula 4. Optionally, R⁴ may be transformed, for example by reductionof R^(4′) when R^(4′) contains a reducible group such as an ester group.The chiral compound 4′ was subsequently obtained by purification usingpreparative chiral HPLC.

I.2. Step 1: Protection and Conversion to Iminoether 1

Method A: Conversion of DMB-Protected Ketopiperazine 1.1 to Iminoether 1

Method A is the procedure used for the synthesis of the iminoetherintermediates 1 with a DMB protecting group and is detailed below:

Method A is illustrated by the synthesis of intermediate 1a whereinR^(4′) is Me.

Synthesis of1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine 1a

Oven-dried (115° C.) sodium carbonate (18.6 g, 98 mmol, 2.25 eq.) wasplaced in a 500 mL round-bottom flask. The round-bottom flask wasbackfilled with Ar and then capped with a rubber septum. A solution of4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one 1.1a (20.6 g, 78 mmol, 1eq.) in anhydrous DCM (250 mL) was added, followed by triethyloxoniumtetrafluoroborate (18.6 g, 98 mmol, 1.25 eq.) in one portion.Thereafter, the reaction mixture was stirred further at RT for 1 hwhereupon the reaction mixture was diluted with water (250 mL). Theaqueous layer was extracted with DCM (3×150 mL). The organic layers werecombined, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude compound was then purified on silica gel (EtOAc) toafford the desired product 1a as orange oil. Yield: 13.2 g, 58%. LCMS:P=93%, retention time=1.8 min, (M+H+H₂O)⁺: 311; ¹H-NMR (CDCl₃): δ 7.23(d, J=8.8 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 6.44 (s, 1H), 4.02 (m, 2H),3.92 (s, 3H), 3.91 (s, 3H), 3.86 (d, J_(AB)=14.0 Hz, 1H), 3.46 (d,J_(AB)=14.0 Hz, 1H), 3.44 (m, 2H), 3.10 (m, 1H), 2.79 (m, 1H), 2.32 (m,1H), 1.35 (d, J=6.8 Hz, 3H), 1.24 (t, J=6.0 Hz, 3H).

I.3. Step 2: Formation of Acyl Hydrazide 2

Method B: Acyl Hydrazide 2

Method B is the procedure used for the synthesis of the acyl hydrazides2 and is detailed below:

In a round-bottom flask equipped with a condenser, ester 2.2 (1 eq.) isdissolved in anhydrous EtOH and treated with hydrazine hydrate (1.2 to20 eq., preferably 1.5 to 10 eq.) using a temperature range from RT toreflux. After allowing the reaction mixture to come to RT, the solutionis concentrated under reduced pressure. Co-evaporations using a mixtureof commercial DCM:MeOH (1:1) may be performed to remove residual water.The residue is then recrystallized and/or precipitated or purified on apad of silica to afford 2.

I.4. Step 3: Cyclodehydration Leading to Triazolopiperazine 3

Method C: Cyclodehydration and acidolysis Method C is the procedure usedfor the synthesis of the triazolopiperazine 3 and is detailed below:

Step 1: In a round-bottom flask equipped with a condenser, imino-ether 1(1 eq.) is dissolved in anhydrous MeOH, to which is added 2 (1 eq.) inone portion. The resulting solution is stirred at reflux overnight.Thereafter, the reaction mixture is brought to RT and the volatiles areremoved under reduced pressure. The crude compound is then purifiedusing silica gel chromatography to afford the desired product 3.1.

Step 2: In a round-bottom flask containing DCM is added 3.1 (1 eq.).Then, TFA (5 to 75 eq.), is added to the reaction mixture at RT. After30 min stirring, the mixture is concentrated. Then DCM is added to theresidue thus obtained, and washed with saturated NaHCO₃. The aqueouslayer is extracted twice with DCM, the organic layers are washed withbrine, dried over MgSO₄, filtered and concentrated under reducedpressure to obtain crude 3. The crude 3 may be directly used in the nextstep without further purification.

In one embodiment, alternative work-up equally used involves treatmentof the dried residue obtained above with 4 M HCl/dioxane (20 eq.) at RTunder stirring. After 5 min, Et₂O is added to help precipitation. Thisprecipitate is filtered off under vacuum, washed with Et₂O and driedunder high vacuum to furnish 3 as hydrochloride salt.

In another embodiment, HCl could be used for Step 2: HCl 4M solution in1,4-dioxane (3 to 20 eq.) is added in one portion to a solution of 3.1(1 eq.) in commercial iso-propanol or ethanol. The reaction mixture isstirred at 60° C. After complete conversion monitored by HPLC-MS (1 to10 h), the reaction mixture is allowed to cool to room temperature andthen further cooled to 0° C. with an ice bath. Thereupon, Et₂O is added.After 15-30 min stirring, the precipitate is filtered and dried in vacuoto afford 3 as hydrochloride salt.

Remark: When R^(5′)≠R⁵═H, introduction of groups such as trifluoro- ordifluoromethyl through direct trifluoromethylation or directdifluoromethylation (Ji Y. et al., PNAS, 2011, 108(35), 14411-14415;Fujiwara Y. et al., JACS, 2012, 134, 1494-1497) may be performed.

I.5. Step 4: Acylation Leading to Final Products

Method D: Acylation and chiral HPLC purification Method D is theprocedure used for the synthesis of the racemic product 4 and itspurification to obtain (R)-enantiomer 4′ compounds of general Formula I.Method D is detailed below:

To a solution of crude 3 (1 eq.) in anhydrous DCM are added, at RT, 4.1(1.17 to 1.3 eq.), followed by N-methylmorpholine (1 eq. to 3.5 eq.)dropwise over 15 sec. The reaction mixture is stirred at RT for 1 to 30minutes and the milky suspension is poured into 1 M HCl solution ordirectly diluted with DCM. The aqueous phase is extracted with DCM. Theorganic phases are combined, optionally washed with 1 M NaOH, water,brine, dried over MgSO₄ and evaporated to dryness. The residue issolubilized in DCM and Et₂O and is slowly added to induce precipitation.The solid was filtered off, washed with Et₂O and dried under vacuum toafford 4. Alternatively, the residue is preliminary purified on silicagel before precipitation or purified on silica gel only.

Substituent R^(4′) may then be transformed, when applicable, into R⁴.One example of such transformation is illustrated by the synthesis ofcompound 12 wherein R⁴ is hydroxyethyl group, obtained by reduction ofR^(4′)═—CH₂CO₂Alkyl.

To a solution of 4 (1 eq.) in anhydrous THF is added, at −40° C., LAH (1eq.), The reaction mixture is stirred at −40° C. for 5 to 30 minutes andthe mixture is quenched with 1 M NaOH solution. The resulting mixture isextracted with DCM twice. The organic phases are combined, dried overMgSO₄ and evaporated to dryness. The residue 4″ is then purified onsilica gel.

Compound 4 or 4″ may be purified by chiral preparative HPLC according tothe abovementioned method to yield the corresponding chiral(R)-compound4′. Compounds 4, 4″ and 4′ are compounds of Formula I of the invention.

II. Chiral Synthesis II.1. General Synthetic Scheme for Chiral Synthesis

Chiral compounds of the invention may be synthesized using the chiralprocess of the invention described in Scheme 7.

Chiral ketopiperazine B was protected with “PG” protecting group leadingto PG-protected chiral ketopiperazine C. PG-protected chiralketopiperazine C was converted to iminoether D by using the Meerweinreagent (Et₃OBF₄). Condensation reaction between the acyl hydrazide Eand iminoether D was conducted under heating conditions in methanol toprovide PG-protected piperazine F that was subsequently deprotected toyield compound of Formula G.

In one embodiment, when the protecting group PG is DMB, the DMB groupdeprotection step (from F to G) is carried out using TFA in DCM at rt,followed by either TFA salt exchange with HCl or extraction at high pHrecovering free piperazine G.

When applicable, R⁵ was introduced from R^(5′) of G, affording G′.

Acylation of G or G′ with the appropriate acid chloride H afforded the(R)-enantiomer of I typically in >90% enantiomeric excess (chiral HPLC).When applicable, R^(4′) of I was then modified to afford R⁴, furnishingI′.

When applicable, R^(5″) of I or I′ was then modified to afford R⁵,furnishing I″ or I′″ respectively.

II.2. Step 1: Protection of Ketopiperazine B II.2.1. Protection ofKetopiperazine B with an Allyl to Afford Protected Ketopiperazine C₁

To a solution of (R)-3-methylpiperazin-2-one (0.5 g, 4.38 mmol) incommercial anhydrous THF (44 mL) at rt was added K₂CO₃ (1.2 g, 8.76mmol). 3-bromoprop-1-ene (0.41 mL, 4.82 mmol) was then added at once,and the reaction mixture was stirred under reflux for 14 h.

The reaction mixture was allowed to cool to rt, concentrated and theresidue was then solubilized with water (10 mL) and DCM (10 mL). Theorganic layer was separated, dried over MgSO₄, filtered and concentratedto afford 460 mg of yellow oil. ¹H-NMR analysis shows that desiredproduct was clearly the main product. Crude was used as-is in thefollowing step.

LCMS: P>90%, retention time=0.2 min, (M+H)⁺: 155. ¹H-NMR (CDCl₃): δ 6.2(m, 1H), 5.8 (m, 1H), 5.3 (m, 2H), 3.4 (m, 3H), 3.3 (q, J 7.2 Hz, 1H),3.1 (m, 2H), 2.6 (m, 1H).

II.2.2. Protection of Ketopiperazine B with DPP to Afford ProtectedKetopiperazine C₂

To a solution of (R)-3-methylpiperazin-2-one (0.5 g, 4.38 mmol) incommercial anhydrous DCM (9 mL) under Ar atmosphere at rt was addeddiphenylphosphinic chloride (0.84 mL, 4.38 mmol) in one portion,followed by N-methylmorpholine (1.2 mL, 8.76 mmol) dropwise. Thereaction mixture was stirred under reflux for 72 h.

The reaction mixture was concentrated and the crude compound was thenpurified on silica gel (DCM/MeOH 99/1) to afford the desired product ascolorless oil. Yield: 0.54 g, 88%. LCMS: P=98%, retention time=2.0 min,(M+H)⁺: 315; chiral HPLC retention time=26.7 min, ee=99.4%; ¹H-NMR(CDCl₃): δ 7.9 (m, 4H), 7.5 (m, 6H), 6.1 (bs, 1H), 3.9 (m, 1H), 3.6 (m,1H), 3.3 (m, 2H), 3.2 (m, 1H), 1.5 (m, 3H).

II.2.3. Protection of Ketopiperazine B with Boc to Afford ProtectedKetopiperazine C₃

To a solution of (R)-3-methylpiperazin-2-one (0.33 g, 2.87 mmol) incommercial anhydrous DCM (10 mL) at 0° C. was added Boc₂O (0.77 mL, 3.30mmol) in one portion. The reaction mixture was allowed to reach rt andstirred for 1 h.

The reaction mixture was concentrated under reduced pressure and theresidue was taken up in DCM (100 mL) and washed with HCl 0.5M (90 mL)and brine (120 mL), dried over MgSO₄, filtered and concentrated underreduced pressure. The crude compound was then purified on silica gel(DCM/MeOH 99/1) to afford the desired product as colorless oil. Yield:0.45 g, 33%. LCMS: P=98%, retention time=1.9 min, (M+H)⁺: 215; ¹H-NMR(CDCl₃): δ 6.3 (bs, 1H), 4.6 (m, 1H), 4.1 (m, 1H), 3.5 (m, 1H), 3.3-3.1(m, 2H), 1.5 (m, 3H), 1.4 (s, 9H).

II.2.4. Protection of Ketopiperazine B with SES to Afford ProtectedKetopiperazine C₄

To a solution of (R)-3-methylpiperazin-2-one (0.25 g, 2.19 mmol) incommercial anhydrous DCM (4.5 mL) under Ar atmosphere at rt was added2-(trimethylsilyl)ethanesulfonyl chloride (0.44 mL, 2.30 mmol) in oneportion, followed by N-methylmorpholine (0.45 mL g, 4.38 mmol) dropwise.The reaction mixture was stirred at rt for 16 h.

The reaction mixture was diluted with water (10 mL) and DCM (10 mL). Theorganic layer was separated, dried over MgSO₄, filtered andconcentrated. The crude compound was then purified on silica gel(DCM/MeOH 99/1) to afford the desired product as colorless oil. Yield:0.08 g, 13%. LCMS: P=95%, retention time=2.1 min, (M+H)⁺: 279; chiralHPLC retention time=7.2 min, ee=99.6%; ¹H-NMR (CDCl₃): δ 6.1 (bs, 1H),4.5 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.9 (m,2H), 1.6 (m, 3H), 1.0 (m, 2H), 0.1 (s, 9H).

II.3. Step 2: Conversion to Iminoether D

Method E: Conversion to Iminoether

General Method E is the procedure used for the synthesis ofintermediates D.

Oven dried (115° C.) sodium carbonate (2.48 g, 23.40 mmol, 2.25 eq.) wasplaced in a round-bottom flask. The round-bottom flask was backfilledwith Ar and then capped with a rubber septum. A solution of(R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one C-1 (2.75 g, 10.40mmol, 1 eq.) in anhydrous DCM (35 mL) was added, followed by freshlyprepared triethyloxonium tetrafluoroborate (2.48 g, 13.05 mmol, 1.25eq.) in one portion. Thereafter the reaction mixture was stirred furtherat rt for 45 min to 1 hour, whereupon the reaction mixture was dilutedwith saturated aqueous NaHCO₃ (100 mL). The aqueous layer was extractedwith DCM (3×200 mL). The organic layers were combined, dried over MgSO₄,filtered and concentrated under reduced pressure to afford 3.1 g ofyellow oil. The crude compound was then purified on silica gel(EtOAc/MeOH: 99/1) to afford the desired product D-1 as a pale yellowoil. Yield: 1.44 g, 48%. LCMS: P=95%, retention time=1.8 min,(M+H2O+H)⁺: 311; chiral HPLC retention time=12.3 min, ee>97%. ¹H-NMR(CDCl₃): δ 7.23 (d, J=8.8, 1H), 6.48 (d, J=8.8, 1H), 6.44 (s, 1H), 4.02(m, 2H), 3.92 (s, 6H), 3.86 (d, J_(AB)=14.0, 1H), 3.46 (d, J_(AB)=14.0,1H), 3.44 (m, 2H), 3.10 (m, 1H), 2.79 (m, 1H), 2.32 (m, 1H), 1.35 (d,J=6.8, 3H), 1.24 (t, J=6.0, 3H).

The reaction mixture may alternatively be treated with brine. Afterstirring far about 20 min, additional water and DCM were added leadingto phase separation. The organic layers were then dried over MgSO₄,filtered and concentrated under reduced pressure. The crude compound wasthen purified on silica gel.

Method E is further illustrated by the synthesis of intermediate(R)-1-allyl-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (i.e. compoundDi wherein PG is allyl and R^(4′) is Me).

To a solution of (R)-4-allyl-3-methylpiperazin-2-one (0.35 g, 2.27 mmol,1 eq.) in DCM (7.6 mL) at 0° C. was added sodium carbonate (0.54 g, 5.11mmol, 2.25 eq.) in one portion, followed by commercial triethyloxoniumtetrafluoroborate (0.54 g, 2.84 mmol, 1.25 eq.) in one portion.Thereafter the reaction mixture was stirred further at rt for 45 min,whereupon the reaction mixture was diluted with DCM (10 mL) and brine(10 mL). The layers were separated and the aqueous layer was furtherextracted with DCM (2×5 mL). The organic layers were combined, driedover MgSO₄, filtered and concentrated under reduced pressure. The crudecompound was then purified on silica gel (EtOAc) to afford the desiredproduct as colorless oil. Yield: 0.19 g, 46%. LCMS: P=95%, retentiontime=1.5 min, (M+H)⁺: 183; ¹H-NMR (CDCl₃): δ 5.9 (m, 1H), 5.2 (m, 2H),4.0 (m, 2H), 3.5 (m, 2H), 3.3 (m, 1H), 3.1-3.0 (m, 2H), 2.8 (m, 1H), 2.4(m, 1H), 1.3 (m, 6H).

The following intermediates were also prepared from the ad hoc reagents:

(R)-(3-ethoxy-2-methyl-5,6-dihydropyrazin-1(2H)-yl)diphenylphosphineoxide in 44% yield. LCMS: P=98%, retention time=2.0 min, (M+H₂O+H)⁺:361; chiral HPLC retention time=4.8 min, ee=99.4%; ¹H-NMR (CDCl₃): δ 7.9(m, 4H), 7.5 (m, 6H), 4.0 (m, 2H), 3.7 (m, 1H), 3.6 (m, 1H), 3.5 (m,1H), 3.1 (m, 2H), 1.4 (m, 3H), 1.2 (m, 3H).

(R)-tert-butyl 3-ethoxy-2-methyl-5,6-dihydropyrazine-1(2H)-carboxylatein 68% yield. LCMS: P=98%, retention time=1.8 min, (M+H₂O+H)⁺: 261;¹H-NMR (CDCl₃): δ 4.3 (m, 1H), 4.1 (m, 2H), 3.9 (m, 1H), 3.5 (m, 2H),2.9 (m, 1H), 1.5 (s, 9H), 1.3 (d, J=6.9 Hz, 3H), 1.2 (t, J=7.0 Hz, 3H).

(R)-5-ethoxy-6-methyl-1-((2-(trimethylsilyl)ethyl)sulfonyl)-1,2,3,6-tetrahydropyrazinein 68% yield. LCMS: P=70%, retention time=2.0 min, (M+H₂O+H)⁺: 325;chiral HPLC retention time=4.8 min, ee=97.3%; ¹H-NMR (CDCl₃): δ 4.3 (m,1H), 4.1 (m, 2H), 3.6 (m, 3H), 3.2 (m, 1H), 2.9 (m, 2H), 1.5 (m, 3H),1.3 (m, 3H), 1.0 (m, 2H), 0.0 (s, 9H).

II.4. Step 3: Cyclodehydration Leading to F

Method F: Cyclodehydration

General Method F is the general procedure used for the synthesis ofchiral triazolopiperazine intermediates F.

Cyclodehydration is illustrated by the synthesis of intermediate(R)-5-(7-allyl-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-methyl-1,2,4-thiadiazole(i.e. compound Fi wherein PG is allyl, R^(4′) is Me, X¹ is N, X² is Sand R^(5′) is methyl).

To (R)-1-allyl-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.14 g,0.77 mmol) at rt was added 3-methyl-1,2,4-thiadiazole-5-carbohydrazide(0.12 g, 0.77 mmol) at once. The mixture was diluted with commerciallyanhydrous MeOH (0.77 mL) to allow complete solubilization and theresulting mixture was heated to 60° C. for 16 h.

The reaction mixture was then allowed to reach rt whereupon the solventwas removed under reduced pressure (1-2 mbar). The crude residue wasthen dissolved in DCM (10 mL), and thus-obtained organic phase washedwith NaOH (1 M, 10 mL). The organic layer was then dried over MgSO₄,filtered and concentrated under reduced pressure (1-2 mbar) the desiredproduct as a yellow solid. Yield: 0.09 g, 42%. LCMS: P=95%, retentiontime=1.6 min, (M+H)⁺: 277; chiral HPLC retention time=21.6 min,ee=98.9%; ¹H-NMR (CDCl₃): δ 5.9 (m, 1H), 5.3 (m, 2H), 4.5 (m, 1H), 4.4(m, 1H), 4.1 (m, 1H), 3.5 (m, 1H), 3.3 (m, 1H), 3.1 (m, 1H), 2.8 (m,1H), 2.7 (s, 3H), 1.6 (m, 3H).

The following intermediates were also prepared from the ad hoc reagents:

(R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)diphenylphosphineoxide in 31% yield (reaction time: 48 h and silica gel purification(EtOAc)). LCMS: P=96%, retention time=2.2 min, (M+H)⁺: 437; chiral HPLCretention time=7.5 min, ee=98.3%; ¹H-NMR (CDCl₃): δ 7.9 (m, 4H), 7.5 (m,6H), 4.9 (m, 1H), 4.8 (dd, J=3.1, 13.6 Hz, 1H), 4.3 (dt, J=4.9, 12.2 Hz,1H), 3.6 (m, 1H), 3.5 (m, 1H), 2.7 (s, 3H), 1.6 (d, J=6.9 Hz, 3H).

(R)-tert-butyl8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylatein 83% yield (reaction time: 48 h). LCMS: P=97%, retention time=2.3 min,(M+H)⁺: 337; chiral HPLC retention time=19.4 min, ee=95.1%; ¹H-NMR(CDCl₃): δ 5.7 (m, 1H), 4.9 (m, 1H), 4.5 (m, 1H), 4.2 (m, 1H), 3.3 (m,1H), 2.7 (s, 3H), 1.6 (d, J=6.9 Hz, 3H), 1.5 (s, 9H).

(R)-3-methyl-5-(8-methyl-7-((2-(trimethylsilyl)ethyl)sulfonyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazolein 28% yield (reaction time: 48 h). LCMS: P=40%, retention time=2.5 min,(M+H)⁺: 401; chiral HPLC retention time=7.1 min, ee=92.4%; ¹H-NMR(CDCl₃): δ 4.9 (m, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.6 (m, 1H), 3.0 (m,1H), 2.7 (s, 3H), 1.6 (m, 2H), 1.4 (m, 3H), 1.0 (m, 2H), 0.0 (s, 9H).

II.5. Step 4: PG-Deprotection

The methods of deprotection of above Protecting Groups (PGs) are knownto those skill-in-the-art. As examples, one may refer to “Greene'sProtective Groups in Organic Synthesis”:

-   -   Allyl: p. 806 of fourth edition;    -   DPP: p. 844 of fourth edition;    -   Boc: p. 725 of fourth edition;    -   SES: p. 854 in fourth edition.

Method G: DMB deprotection—TFA/DCM

Deprotection of DMB may be performed using TFA.

When crude or precipitated F was used (in opposition to purified F onsilica gel), pre-washing was performed before deprotection as follow: Fwas dissolved in DCM and optionally washed with 1M NaOH in order toremove remaining E. The DCM extracts were then dried over magnesiumsulphate, filtered and the filter cake washed with DCM.

F was diluted with DCM and TFA (7.6 eq.) was added to the DCM solutionof F at RT. The mixture was stirred at rt for 2 h-2 h30. Completion ofthe deprotection was monitored by HPLC. Water was added, the mixturestirred for 30 minutes and filtered. The filter cake was washed withwater and DCM. The filtrate layers were separated. The pH of the aqueouslayer was adjusted to 12-13 by the addition of 4M NaOH. Sodium chloridewas then added and the aqueous solution was extracted with DCM. The DCMextract comprising G was concentrated and was used in the next stepwithout further purification. II.6. Optional conversion of R^(5′) to R⁵in triazolopiperazine

Substituent R⁵ may then be introduced, when applicable, from R^(5′)(especially when R^(5′) ═H). One example of such transformation isillustrated by the synthesis of intermediate G′ wherein R⁵ istrifluoromethyl.

To a solution of G (1 eq.) in DCM/water (3/1) are added, at rt, sodiumtrifluoromethansulfonate (3 eq.) and 2-hydroperoxy-2-methylpropane (5eq.). The reaction mixture is not stirred and left at rt. Monitoringconversion by HPLC-MS, extra amount of each reagent can be added ifrequired. The resulting mixture is diluted with DCM and quenched with 4M NaOH saturated solution. Layers were separated and aqueous layer wasextracted twice with EtOAc. The organic phases are combined, dried overMgSO₄ and evaporated to dryness. The residue is purified on silica gelor used crude in next step.

A further example of such transformation is illustrated by the synthesisof intermediate G′ wherein R⁵ is difluoromethyl:

To a suspension of G (R^(5′)═H)(R)-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole(0.29 g, 1.13 mmol) and bis(difluoromethylsulfinyloxy)zinc (0.67 g, 2.26mmol) in DCM (5 mL) and Water (2 mL), was added TFA (0.09 mL, 1.13mmol), followed by slow addition of 2-hydroperoxy-2-methylpropane (0.77mL, 5.64 mmol) with vigorous stirring.

When conversion was not increasing any more (HPLC-MS monitoring)bis(difluoromethylsulfinyloxy)zinc and 2-hydroperoxy-2-methylpropanewere added at rt still with vigorous stirring (3 additional times (1.001g, 3.39 mmol) and (0.773 mL, 5.64 mmol) respectively).

After 4 days in total, reaction mixture was diluted with EtOAc (50 mL)and carefully quenched with NaHCO₃sat. solution (30 mL) and then NaHCO₃solid until no bubbling was observed. Reaction mixture was filtered onCelite pad and phases of the filtrate were separated. Aqueous phase wasfiltered again on Celite pad then filtrate was extracted with EtOAc(2×50 mL). Organic phases were combined, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude compound was thenpurified on silica gel (DCM/MeOH 99/1) to afford the desired product ascolorless oil. Yield: 0.03 g, 10%. LCMS: P=97%, retention time=1.8 min,(M+H)⁺: 273; ¹H-NMR (CDCl₃): δ 6.8 (t, J_(H-F)=53.5 Hz, 1H), 4.7 (m,1H), 4.3 (m, 2H), 3.5 (m, 1H), 3.3 (m, 1H), 1.7 (d, J=6.7 Hz, 3H);¹⁹F-NMR (CDCl₃): δ −113.5 (dd, J=3.2, 53.5 Hz, 2F).

II.7. Step 5: Acylation Leading to Products I

Method H: Acylation NMM/DCM

General Method H is the general procedure used for the synthesis of(R)-enantiomer of Formula I of the invention.

To a solution of crude G or G′ (1 eq.) in anhydrous DCM were added at 0°C. H (1.3 eq.), followed by N-methylmorpholine (2.2 eq.) dropwise over15 sec. The reaction mixture was stirred at rt for 10 minutes and, themilky suspension was poured into 1 M HCl. The aqueous phase wasextracted with DCM. The organic phases were combined, washed with 1 MNaOH, brine, dried over MgSO₄ and evaporated to dryness. The crudecompound was purified by silica gel chromatography to afford the desiredproduct (R)-I.

Measurement of % ee confirmed that no detectable racemization occursduring the acidolytic deprotection and N-acylation steps.

Method I: Acylation—Biphasic Conditions

Alternatively, the reaction may be performed under biphasic conditions.

In this case, saturated sodium hydrogen carbonate solution was added tothe DCM slurry of G or G′ (1 eq.) at rt. H (1 eq.) was added and themixture stirred for a period of time ranging from about 20 minutes toovernight at rt. Completion of the reaction was monitored by HPLC. Thelayers were separated and the DCM phase washed with water. The DCMextracts were dried with magnesium sulphate and filtered, washing thefilter cake with DCM. The DCM extracts were then concentrated. TBME wasadded and the resulting slurry stirred overnight at rt. The solid wascollected by filtration, washed with TBME and pulled dry. The crudecompound may be purified by silica gel chromatography or bycrystallisation.

Measurement of % ee confirmed that no detectable racemization occursduring the acidolytic deprotection and N-acylation steps.

Substituent R^(4′) may then be transformed, when applicable, into R⁴(see racemic synthesis).

II.8. Optional Further Transformation Leading to Products I″/I′″ fromI/I′

Compound 45: From compound I/I′ whereinR^(5″)=1-((tert-butyldiphenylsilyl)oxy)ethyl, well knowntert-butylammonium fluoride TBDPS deprotection of alkoxy was applied,followed by DAST fluorination of the latter alcohol, leading to racemiccompound 45. Both diastereomers can be separated by purification onpreparative HPLC to afford 45-1 and 45-2.

Compound 43: From compound I/I′ whereinR^(5″)=1-((tert-butyldiphenylsilyl)oxy)ethyl, well knowntert-butylammonium fluoride TBDPS deprotection of alkoxy was applied,followed by Dess-Martin oxidation, then followed by DAST fluorination ofthe latter ketone, leading to compound 43.

III. Chemical Characterization

Compound 1: HPLC-MS: t_(R)=4.1 min, (M+H)⁺=409; Chiral HPLC (Method C):% ee=99.0; ¹H-NMR (CDCl₃): δ 7.6 (m, 2H), 7.3 (m, 1H), 5.8 (m, 1H), 4.9(m, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 3.6 (m, 1H), 2.7 (s, 3H), 1.7 (d,3H).

Compound 2: HPLC-MS: t_(R)=3.8 min, (M+H)⁺=373; Chiral HPLC (Method A):% ee=98.0; ¹H-NMR (300 MHz, CDCl₃): δ 7.5 (m, 2H), 7.2 (m, 2H), 5.8 (m,1H), 4.9 (dd, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 3.6 (m, 1H), 3.1 (q, 2H),1.8 (d, 3H), 1.4 (t, 3H); ¹⁹F-NMR (CDCl₃): δ −98.5.

Compound 3: HPLC-MS: t_(R)=3.8 min, (M+H)⁺=375; Chiral HPLC (Method C):% ee>99.8; ¹H-NMR (CDCl₃): δ 7.5 (m, 4H), 5.8 (m, 1H), 4.9 (m, 1H), 4.6(m, 1H), 4.3 (m, 1H), 3.6 (m, 1H), 2.7 (s, 3H), 1.7 (d, 3H).

Compound 4: HPLC-MS: t_(R)=3.9 min, (M+H)⁺=393; Chiral HPLC (Method C):% ee=99.0; ¹H-NMR (CDCl₃): δ 7.6 (m, 1H), 7.3 (s, 1H), 7.2 (m, 1H), 5.8(m, 1H), 4.9 (m, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 3.6 (m, 1H), 2.7 (s,3H), 1.7 (d, 3H); ¹⁹F-NMR (CDCl₃): δ −98.4.

Compound 5: HPLC-MS: t_(R)=3.4 min, (M+H)⁺=359; Chiral HPLC (Method C):% ee=99.0; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.3 (m, 2H), 5.8 (m, 1H), 4.9(m, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 3.5 (m, 1H), 2.7 (s, 3H), 1.7 (d,3H); ¹⁹F-NMR (CDCl₃): δ −98.4.

Compound 6: HPLC-MS: t_(R)=3.8 min, (M+H)⁺=393; Chiral HPLC (Method C):% ee=99.5; ¹H-NMR (CDCl₃): δ 7.6 (m, 1H), 7.3 (m, 2H), 5.7 (m, 1H), 4.9(m, 1H), 4.5 (m, 1H), 4.3 (m, 1H), 3.5 (m, 1H), 2.7 (s, 3H), 1.8 (d,3H); ¹⁹F-NMR (CDCl₃): δ −96.2.

Compound 7: HPLC-MS: t_(R)=3.8 min, (M+H)⁺=395; Chiral HPLC (Method C):% ee=98.9; ¹H-NMR (CDCl₃): δ 7.1 (m, 2H), 5.8 (m, 1H), 5.0 (m, 1H), 4.5(m, 1H), 4.3 (m, 1H), 3.6 (m, 1H), 2.7 (s, 3H), 1.8 (d, 3H); ¹⁹F-NMR(CDCl₃): δ −75.8.

Compound 8: HPLC-MS: t_(R)=3.7 min, (M+H)⁺=395; Chiral HPLC (Method C):% ee=99.0; ¹H-NMR (CDCl₃): δ 7.1 (m, 2H), 6.2 (m, 1H), 5.3-5.0 (m, 2H),4.3-3.6 (m, 2H), 2.7 (s, 3H), 1.8 (m, 3H); ¹⁹F-NMR (CDCl₃): δ −49.4,−72.0, −77.4.

Compound 9: HPLC-MS: t_(R)=3.6 min, (M+H)⁺=377; Chiral HPLC (Method C):% ee=99.4; ¹H-NMR (CDCl₃): δ 7.3 (m, 3H), 5.8 (m, 1H), 4.9 (dd, 1H), 4.6(m, 1H), 4.3 (td, 1H), 3.6 (td, 1H), 2.7 (s, 3H), 1.7 (d, 3H); ¹⁹F-NMR(CDCl₃): δ −72.1, −74.4.

Compound 10: HPLC-MS: t_(R)=4.0 min, (M+H)⁺=413; Chiral HPLC (Method C):% ee=99.0; ¹H-NMR (CDCl₃): δ 7.2 (m, 1H), 6.2 (m, 1H), 5.2-5.0 (m, 2H),4.3 (m, 1H), 3.9-3.4 (m, 2H), 2.7 (s, 3H), 1.8 (m, 3H); ¹⁹F-NMR (CDCl₃):δ −54.2, −56.3, −67.1, −72.8.

Compound 11: HPLC-MS: t_(R)=3.2 min, (M+H)⁺=389; Chiral HPLC (Method A):% ee>99.8; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.2 (m, 2H), 6.1 (m, 1H), 4.9(dd, 1H), 4.3 (m, 2H), 3.9 (m, 2H), 3.6 (m, 1H), 2.7 (s, 3H), 2.4 (m,1H), 2.2 (m, 1H); ¹⁹F-NMR (CDCl₃): δ −97.9.

Compound 12: is racemate of compound 11.

Compound 13: HPLC-MS: t_(R)=4.1 min, (M+H)⁺=357; Chiral HPLC (Method B):% ee=98.7; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.2 (m, 2H), 5.8 (m, 1H), 4.8(dd, 1H), 4.6 (m, 1H), 4.3 (td, 1H), 3.6 (td, 1H), 2.9 (q, 2H), 1.8 (d,3H), 1.4 (t, 3H); ¹⁹F-NMR (CDCl₃): δ −98.7.

Compound 14: is racemate of compound 5.

Compound 15: HPLC-MS: t_(R)=3.4 min, (M+H)⁺=359; Chiral HPLC (Method B):% ee>99.8; ¹H-NMR (CDCl₃): δ 7.5 (m, 1H), 7.2 (m, 3H), 5.8 (m, 1H), 4.9(dd, 1H), 4.6 (m, 1H), 4.3 (td, 1H), 3.6 (td, 1H), 2.7 (s, 3H), 1.7 (d,3H); ¹⁹F-NMR (CDCl₃): δ −96.2.

Compound 16: HPLC-MS: t_(R)=3.7 min, (M+H)⁺=375; ¹H-NMR (CDCl₃): δ7.5-7.3 (m, 4H), 5.8 (m, 1H), 4.9 (dd, 1H), 4.6 (m, 1H), 4.3 (td, 1H),3.6 (td, 1H), 2.7 (s, 3H), 1.7 (d, 3H).

Compound 17: HPLC-MS: t_(R)=3.6 min, (M+H)⁺=377; ¹H-NMR (CDCl₃): δ 7.3(m, 1H), 7.0 (m, 2H), 5.8 (m, 1H), 4.9 (dd, 1H), 4.6 (m, 1H), 4.3 (td,1H), 3.6 (td, 1H), 2.8 (s, 3H), 1.8 (d, 3H); ¹⁹F-NMR (CDCl₃): δ −101.2.

Compound 18: HPLC-MS: t_(R)=3.5 min, (M+H)⁺=377; ¹H-NMR (CDCl₃): δ 7.5(m, 1H), 7.0-6.9 (m, 2H), 6.2 (m, 1H), 5.2-4.9 (m, 2H), 4.3 (m, 1H),4.0-3.7 (m, 1H), 2.7 (s, 3H), 1.7 (m, 3H); ¹⁹F-NMR (CDCl₃): δ −95.7,−102.5.

Compound 19: HPLC-MS: t_(R)=3.6 min, (M+H)⁺=355; ¹H-NMR (CDCl₃): δ 7.4(m, 4H), 5.8 (m, 1H), 4.9 (dd, 1H), 4.6 (m, 1H), 4.3 (td, 1H), 3.6 (td,1H), 2.7 (s, 3H), 2.4 (s, 3H), 1.7 (d, 3H).

Compound 20: HPLC-MS: t_(R)=3.3 min, (M+H)⁺=341; Chiral HPLC (Method C):% ee=96.8; ¹H-NMR (CDCl₃): δ 7.5 (m, 5H), 5.8 (m, 1H), 4.9 (dd, 1H), 4.6(m, 1H), 4.3 (td, 1H), 3.6 (td, 1H), 2.7 (s, 3H), 1.7 (d, 3H).

Compound 21: HPLC-MS: t_(R)=4.0 min, (M+H)⁺=409; ¹H-NMR (CDCl₃): δ 7.7(d, 2H), 7.6 (d, 1H), 5.8 (m, 1H), 4.9 (dd, 1H), 4.6 (m, 1H), 4.3 (td,1H), 3.6 (m, 1H), 2.7 (s, 3H), 1.7 (d, 3H); ¹⁹F-NMR (CDCl₃): δ −60.1.

Compound 22: HPLC-MS: t_(R)=3.7 min, (M+H)⁺=373; Chiral HPLC (Method B):% ee>99.7; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.3 (m, 2H), 5.8 (m, 1H), 4.9(dd, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 3.6 (m, 1H), 2.7 (s, 3H), 2.2-2.0(m, 2H), 1.1 (m, 3H); ¹⁹F-NMR (CDCl₃): δ −98.4.

Compound 23: is racemate of compound 22.

Compound 24: HPLC-MS: t_(R)=4.0 min, (M+H)⁺=387; Chiral HPLC (Method D):% ee=95.5; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.2 (m, 2H), 5.8 (m, 1H), 4.9(m, 1H), 4.6 (m, 1H), 4.2 (m, 1H), 3.6 (m, 1H), 2.7 (s, 3H), 2.1-2.0 (m,2H), 1.6 (m, 2H), 1.0 (m, 3H); ¹⁹F-NMR (CDCl₃): δ −98.2.

Compound 25: HPLC-MS: t_(R)=3.5 min, (M+H)⁺=389; ¹H-NMR (CDCl₃): δ 7.2(m, 2H), 7.0 (m, 2H), 5.8 (m, 1H), 4.9 (dd, 1H), 4.6 (m, 1H), 4.3 (td,1H), 3.9 (s, 3H), 3.5 (td, 1H), 2.7 (s, 3H), 1.8 (d, 3H); ¹⁹F-NMR(CDCl₃): δ −76.3.

Compound 26: HPLC-MS: t_(R)=3.5 min, (M+H)⁺=355; ¹H-NMR (CDCl₃): δ7.4-7.2 (m, 4H), 6.3 (m, 1H), 5.3-4.8 (m, 2H), 4.3-3.8 (m, 1H), 3.5-3.4(m, 1H), 2.7 (2s, 3H), 2.3 (s, 3H). 1.7 (2s, 3H).

Compound 27: HPLC-MS: t_(R)=3.4 min, (M+H)⁺=371; ¹H-NMR (CDCl₃): δ7.4(m, 1H), 7.0 (m, 3H), 5.8 (m, 1H), 4.9 (dd, 1H), 4.6 (m, 1H), 4.3 (td,1H), 3.8 (s, 3H), 3.5 (td, 1H), 2.7 (s, 3H), 1.7 (d, 3H).

Compound 28: HPLC-MS: t_(R)=3.1 min, (M+H)⁺=343; Chiral HPLC (Method C):% ee=96.1; ¹H-NMR (CDCl₃): δ7.5 (m, 2H), 7.2 (m, 2H), 5.8 (m, 1H), 4.9(dd, 1H), 4.6 (m, 1H), 4.3 (td, 1H), 3.5 (td, 1H), 2.5 (s, 3H), 1.7 (d,3H); ¹⁹F-NMR (CDCl₃): δ −98.3.

Compound 29: HPLC-MS: t_(R)=3.2 min, (M+H)⁺=366; Chiral HPLC (Method B):% ee=99.0; ¹H-NMR (CDCl₃): δ 7.8 (d, 2H), 7.6 (d, 2H), 5.8 (m, 1H), 4.9(dd, 1H), 4.6 (m, 1H), 4.3 (td, 1H), 3.6 (td, 1H), 2.7 (s, 3H), 1.7 (d,3H).

Compound 30: HPLC-MS: t_(R)=4.9 min, (M+H)⁺=421; Chiral HPLC (Method A):% ee=98.2; ¹H-NMR (CDCl₃): δ7.7 (d, 2H), 7.5 (d, 2H), 7.4 (m, 2H), 7.1(m, 1H), 5.9 (m, 1H), 4.8 (dd, 1H), 4.7 (m, 1H), 4.3 (td, 1H), 3.6 (td,1H), 2.9 (q, 2H), 1.8 (d, 3H), 1.4 (t, 3H).

Compound 31: is racemate of compound 10.

Compound 32: is racemate of compound 9.

Compound 33: is racemate of compound 8.

Compound 34: is racemate of compound 7.

Compound 35: is racemate of compound 6.

Compound 36: is racemate of compound 4.

Compound 37: is racemate of compound 3.

Compound 38: is racemate of compound 1.

Compound 39: is racemate of compound 2.

Compound 40: is racemate of compound 13.

Compound 41: HPLC-MS: t_(R)=4.8 min, (M+H)⁺=413; Chiral HPLC (Method B):% ee=99.7; ¹H-NMR (CDCl₃): δ7.5 (m, 2H), 7.2 (m, 2H), 5.8 (m, 1H), 4.9(dd, 1H), 4.6 (m, 1H), 4.3 (td, 1H), 3.6 (td, 1H), 1.8 (d, 3H); ¹⁹F-NMR(CDCl₃): δ −62.9, −98.7.

Compound 42: HPLC-MS: t_(R)=4.3 min, (M+H)⁺=395; Chiral HPLC (Method B):% ee=97.4; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.1 (m, 2H), 6.8 (t,J_(H-F)=53.5 Hz, 1H), 5.8 (m, 1H), 4.9 (dd, J=3.1, 13.6 Hz, 1H), 4.6 (m,1H),), 4.3 (dt, J=4.6, 13.3 Hz, 1H), 3.6 (m, 1H), 1.8 (d, J=6.9 Hz, 3H);¹⁹F-NMR (CDCl₃): δ −105.2 (s, 1F), −113.4 (dd, J=9.6, 53.4 Hz, 2F).

Compound 43: HPLC-MS: t_(R)=4.4 min, (M+H)⁺=393; Chiral HPLC (Method C):% ee=96.3; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.2 (m, 2H), 5.9 (m, 1H), 4.8(dd, J=3.3, 13.5 Hz, 1H), 4.6 (m, 1H), 4.3 (dt, J=4.2, 12.7 Hz, 1H), 3.6(m, 1H), 2.2 (t, J=8.6 Hz, 3H), 1.8 (d, J=6.9 Hz, 3H); ¹⁹F-NMR (CDCl₃):δ −88.3 (q, J=18.3 Hz, 2F), −105.0 (s, 1F).

Compound 44: HPLC-MS: t_(R)=4.4 min, (M+H)⁺=411; Chiral HPLC (Method C):% ee=98.6; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.2 (m, 2H), 5.8 (m, 1H), 4.8(dd, J=3.5, 13.6 Hz, 1H), 4.6 (m, 1H), 4.3 (dt, J=4.0, 12.2 Hz, 1H), 3.7(q, J=10.0 Hz, 2H), 3.6 (m, 1H), 1.8 (d, J=6.9 Hz, 3H); ¹⁹F-NMR (CDCl₃):δ −61.1 (t, J=9.6 Hz, 1F), −105.0 (s, 1F).

Compound 45: HPLC-MS: t_(R)=4.4 min, (M+H)⁺=375; Chiral HPLC (Method C):% ee=98.5; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.2 (m, 2H), 5.9 (m, 1H), 5.8(m, 1H), 4.9 (m, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 3.6 (m, 1H), 1.9 (d,J=6.9 Hz, 3H), 1.8 (m, 3H); ¹⁹F-NMR (CDCl₃): δ −105.0 (s, 1F), −175.0(m, 1F).

Compound 45-1: HPLC-MS: t_(R)=4.4 min, (M+H)⁺=375; Chiral HPLC (MethodC): % ee=99.2; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.2 (m, 2H), 5.9 (m, 1H),5.8 (m, 1H), 4.9 (m, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 3.6 (m, 1H), 1.9 (d,J=6.9 Hz, 3H), 1.8 (m, 3H); ¹⁹F-NMR (CDCl₃): δ −105.0 (s, 1F), −175.0(m, 1F).

Compound 45-2: HPLC-MS: t_(R)=4.4 min, (M+H)⁺=375; Chiral HPLC (MethodC): % ee=91.7; ¹H-NMR (CDCl₃): δ 7.5 (m, 2H), 7.2 (m, 2H), 5.9 (m, 1H),5.8 (m, 1H), 4.9 (m, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 3.6 (m, 1H), 1.9 (d,J=6.9 Hz, 3H), 1.8 (m, 3H); ¹⁹F-NMR (CDCl₃): δ −105.0 (s, 1F), −175.0(m, 1F).

Biology Examples

Functional Assay

Aequorin Assay with Human NK-3 Receptor

Changes in intracellular calcium levels are a recognized indicator of Gprotein-coupled receptor activity. The efficacy of compounds of theinvention to inhibit NKA-mediated NK-3 receptor activation was assessedby an in vitro Aequorin functional assay. Chinese Hamster Ovaryrecombinant cells expressing the human NK-3 receptor and a constructthat encodes the photoprotein apoaequorin were used for this assay. Inthe presence of the cofactor coelenterazine, apoaequorin emits ameasurable luminescence that is proportional to the amount ofintracellular (cytoplasmic) free calcium.

Antagonist Testing

The antagonist activity of compounds of the invention is measuredfollowing pre-incubation (3 minutes) of the compound (at variousconcentrations) with the cells, followed by addition of the referenceagonist (NKA) at a final concentration equivalent to the EC₈₀ (3 nM) andrecording of emitted light (FDSS 6000 Hamamatsu) over the subsequent90-second period. The intensity of the emitted light is integrated usingthe reader software. Compound antagonist activity is measured based onthe concentration-dependent inhibition of the luminescence response tothe addition of Neurokinin A.

Inhibition curves are obtained for compounds of the invention and theconcentrations of compounds which inhibit 50% of reference agonistresponse (IC₅₀) were determined (see results in table 2 below). The IC₅₀values shown in table 2 indicate that compounds of the invention arepotent NK-3 antagonist compounds.

Competitive Binding Assays

The affinity of compounds of the invention for the human NK-3 receptorwas determined by measuring the ability of compounds of the invention tocompetitively and reversibly displace a well-characterized NK-3radioligand in a concentration-dependent manner.

³H-SB222200 Binding Competition Assay with Human NK-3 Receptor

The ability of compounds of the invention to inhibit the binding of theNK-3 receptor selective antagonist ³H-SB222200 was assessed by an invitro radioligand binding assay. Membranes were prepared from Chinesehamster ovary recombinant cells stably expressing the human NK-3receptor. The membranes were incubated with 5 nM ³H-SB222200 (ARC) in aHEPES 25 mM/NaCl 0.1M/CaCl₂ 1 mM/MgCl₂ 5 mM/BSA 0.5%/Saponin 10 μg/mlbuffer at pH 7.4 and various concentrations of compounds of theinvention. The amount of ³H-SB222200 bound to the receptor wasdetermined after filtration by the quantification of membrane associatedradioactivity using the TopCount-NXT reader (Packard). Competitioncurves were obtained for compounds of the invention and theconcentration that displaced 50% of bound radioligand (IC₅₀) weredetermined by linear regression analysis and then the apparentinhibition constant (K_(i)) values were calculated by the followingequation: K_(i)=IC₅₀/(1+[L]/K_(d)) where [L] is the concentration offree radioligand and K_(d) is its dissociation constant at the receptor,derived from saturation binding experiments (Cheng and Prusoff, 1973)(see results in table 2 below).

Table 2 shows biological results obtained using the ³H-SB222200 bindingcompetition assay with compounds of the invention. These resultsindicate that compounds of the invention display potent affinity for thehuman NK-3 receptor.

TABLE 2 Functional assay: Aequorin Competitive binding assay with humanNK-3 receptor assaywith human Cpd hNK-3 - AEQ(antagonist NK-3 receptorno IC₅₀, nM) hNK-3 (K_(i), nM)  1 16 11  2 12 15  3 32 19  4 19 20  5 1823  6 30 24  7 30 26  8 33 26  9 21 30 10 56 31 11 73 32 12 170 59 13 4440 14 57 42 15 50 45 16 71 49 17 50 51 18 87 54 19 110 56 20 93 60 21150 63 22 130 69 23 220 150 24 120 78 25 110 85 26 74 88 27 220 100 28160 110 29 170 150 30 5 7 31 64 70 32 44 59 33 120 89 34 62 38 35 54 7336 58 43 37 52 41 38 34 26 39 32 28 40 130 83 41 7 11 42 39 48 43 136 5944 204 45 45 244 101 45-1 285 100 45-2 148 83

Selectivity Assay

Selectivity of the compounds of the invention was determined over theother human NK receptors, namely NK-1 and NK-2 receptors.

Human NK-1

The affinity of compounds of the invention for the NK-1 receptor wasevaluated in CHO recombinant cells which express the human NK-1receptor. Membrane suspensions were prepared from these cells. Thefollowing radioligand: [³H] substance P (PerkinElmer Cat #NET111520) wasused in this assay. Binding assays were performed in a 50 mM Tris/5 mMMnCl2/150 mM NaCl/0.1% BSA at pH 7.4. Binding assays consisted of 25 μlof membrane suspension (approximately 5 μg of protein/well in a 96 wellplate), 50 μl of compound or reference ligand (Substance P) atincreasing concentrations (diluted in assay buffer) and 2 nM [³H]substance P. The plate was incubated 60 min at 25° C. in a water bathand then filtered over GF/C filters (Perkin Elmer, 6005174, presoaked in0.5% PEI for 2 h at room temperature) with a Filtration unit (PerkinElmer). The radioactivity retained on the filters was measured by usingthe TopCount-NXT reader (Packard). Competition curves were obtained forcompounds of the invention and the concentrations of compounds whichdisplaced 50% of bound radioligand (IC₅₀) were determined and thenapparent inhibition constant Ki values were calculated by the followingequation: Ki=IC₅₀/(1+[L]/K_(D)) where [L] is the concentration of freeradioligand and K_(D) is its dissociation constant at the receptor,derived from saturation binding experiments (Cheng and Prusoff, 1973).

Human NK-2

The affinity of compounds of the invention for the NK-2 receptor wasevaluated in CHO recombinant cells which express the human NK-2receptor. Membrane suspensions were prepared from these cells. Thefollowing radioligand [¹²⁵I]-Neurokinin A (PerkinElmer Cat #NEX252) wasused in this assay. Binding assays were performed in a 25 mM HEPES/1 mMCaCl₂)/5 mM MgCl2/0.5% BSA/10 μg/ml saponin, at pH 7.4. Binding assaysconsisted of 25 μl of membrane suspension (approximately 3.75 μg ofprotein/well in a 96 well plate), 50 μl of compound or reference ligand(Neurokinin A) at increasing concentrations (diluted in assay buffer)and 0.1 nM [¹²⁵I]-Neurokinin A. The plate was incubated 60 min at 25° C.in a water bath and then filtered over GF/C filters (Perkin Elmer,6005174, presoaked in assay buffer without saponine for 2 h at roomtemperature) with a Filtration unit (Perkin Elmer). The radioactivityretained on the filters was measured by using the TopCount-NXT reader(Packard). Competition curves were obtained for compounds of theinvention and the concentrations of compounds which displaced 50% ofbound radioligand (IC₅₀) were determined and then apparent inhibitionconstant Ki values were calculated by the following equation:Ki=IC₅₀/(1+[L]/K_(D)) where [L] is the concentration of free radioligandand K_(D) is its dissociation constant at the receptor, derived fromsaturation binding experiments (Cheng and Prusoff, 1973).

The compounds of the invention, which were tested in the above NK-1 andNK-2 described assays, demonstrated a low affinity at the human NK-1 andhuman NK-2 receptors: more than 200 fold shift of the K_(i) compared tothe human NK-3 receptor (table 3). Thus, compounds according to theinvention have been shown to be selective over NK-1 and NK-2 receptors.

TABLE 3 Cpd no hNK-3 (K_(i), nM) hNK-1 (K_(i), nM) hNK-2 (K_(i), nM)  111 10300 7500  2 15 23800 >30000  3 19 >30000 >30000  4 20 19900 23000 5 23 >30000 >30000  6 24 22100 25000  7 26 >30000 36000  826 >30000 >30000  9 30 >30000 >30000 10 31 >30000 49000 11 3222000 >30000 12 59 NA NA 13 40 >30000 >30000 14 42 >30000 >30000 1545 >30000 >30000 16 49 >30000 37000 17 51 >30000 >30000 1854 >30000 >30000 19 56 >30000 >30000 20 60 >30000 >30000 2163 >30000 >30000 22 69 >30000 >30000 23 150 NA NA 24 78 >30000 >30000 2585 >30000 >30000 26 88 >30000 >30000 27 100 >30000 >30000 28110 >30000 >30000 29 150 >30000 >30000 30 7 40000 32000 3170 >30000 >30000 32 59 >30000 >30000 33 89 >30000 >30000 3438 >30000 >30000 35 73 >30000 30000 36 43 >30000 36000 37 4132000 >30000 38 26 21000 28000 39 28 >30000 >30000 40 83 >30000 >3000041 11 NA NA 42 48 >30000 >30000 43 59 >30000 >30000 44 45 >30000 >3000045 101 >30000 >30000 45-1 100 >30000 >30000 45-2 83 >30000 >30000 NA:not available

hERG Inhibition Assay

The human ether-a-go-go related gene (hERG) encodes the inwardrectifying voltage gated potassium channel in the heart (I_(Kr)) whichis involved in cardiac repolarisation. I_(Kr) current inhibition hasbeen shown to elongate the cardiac action potential, a phenomenonassociated with increased risk of arrhythmia. I_(Kr) current inhibitionaccounts for the vast majority of known cases of drug-inducedQT-prolongation. A number of drugs have been withdrawn from late stageclinical trials due to these cardiotoxic effects, therefore it isimportant to identify inhibitors early in drug discovery.

The hERG inhibition study aims at quantifying the in vitro effects ofcompounds of the invention on the potassium-selective IK_(r) currentgenerated in normoxic conditions in stably transfected HEK 293 cellswith the human ether-a-go-go-related gene (hERG).

Whole-cell currents (acquisition by manual patch-clamp) elicited duringa voltage pulse were recorded in baseline conditions and followingapplication of tested compounds (5 minutes of exposure). Theconcentrations of tested compounds (0.3 μM; 3 μM; 10 μM; 30 μM) reflecta range believed to exceed the concentrations at expected efficacy dosesin preclinical models.

The pulses protocol applied is described as follow: the holdingpotential (every 3 seconds) was stepped from −80 mV to a maximum valueof +40 mV, starting with −40 mV, in eight increments of +10 mV, for aperiod of 1 second. The membrane potential was then returned to −55 mV,after each of these incremented steps, for 1 second and finallyrepolarized to −80 mV for 1 second.

The current density recorded were normalized against the baselineconditions and corrected for solvent effect and time-dependent currentrun-down using experimental design in test compound free conditions.

Inhibition curves were obtained for compounds and the concentrationswhich decreased 50% of the current density determined in the baselineconditions (IC₅₀) were determined. All compounds for which the IC₅₀value is above 10 μM are not considered to be potent inhibitors of thehERG channel whereas compounds with IC₅₀ values below 1 μM areconsidered potent hERG channel inhibitors.

When tested in the hERG inhibition assay, compounds of the inventionwere determined to have IC₅₀ values as shown in Table 4.

Determination of plasma protein binding The pharmacokinetic andpharmacodynamic properties of chemicals/drugs are largely a function ofthe reversible binding of chemicals to plasma or serum proteins.Generally, only the unbound or “free fraction” of a drug is availablefor diffusion or transport across cell membranes, and for interactionwith a pharmacological/toxicological target. Consequently, the extent ofthe plasma protein binding (PPB) of a compound influences its action aswell as its distribution and elimination.

The determination of plasma protein binding (PPB) of a compound isenabled by equilibrium dialysis, an accepted and standard method forreliable estimation of the non-bound drug fraction in plasma. RED (RapidEquilibrium Dialysis) device insert is made of two side-by-side chambersseparated by an O-ring-sealed vertical cylinder of dialysis membrane(MWCO ˜8,000). Plasma containing drug (at 5 μM or blood concentrationsotherwise corresponding to efficacious doses, if known) is added to onechamber while buffer is added to the second. After 4 hours incubation at37° C. under shaking, an aliquot is removed from each chamber andanalyzed by a LC-MS/MS procedure enables the determination of both freeand bound drug.

The percentages provided in Table 4 represent for the compounds of theinvention the bound drug fraction to the plasma protein. The “freefraction” may be calculated as 100%−% rPPB (i.e. the complementarypercentage of that disclosed in Table 4, corresponding to the drugconcentration that is unbound and therefore available to engagebiological target and elicit pharmacological activity).

TABLE 4 Cpd no Exposure (% rPPB) CardioSafety (hERG IC₅₀, μM)  1 67 42 2 47 32  3 42 66  4 40 70  5 22 70  6 53 45  7 26 70  8 29 70  9 22 7010 30 70 11 24 50 12 20 NA 13 37 70 14 21 NA 15 20 70 16 36 70 17 24 4618 23 70 19 51 NA 20 26 50 21 38 45 22 27 70 23 34 NA 24 48 61 25 19 NA26 19 NA 27 24 70 28 12 NA 29 10 59 30 94 32 31 31 NA 32 25 NA 33 29 NA34 24 NA 35 52 NA 36 60 NA 37 53 NA 38 76 NA 39 43 NA 40 24 NA 41 55 NA42 16 NA 43 47 NA 44 31 NA 45 31 NA 45-1 27 NA 45-2 33 NA NA: notavailable

In Vivo Assay to Assess Compound Activity in Rat (Oral Dosing)

Castrated male rat model to assess the effect of compound of inventionon circulating levels of luteinizing hormone (LH)

The effect of compounds of the invention to inhibit luteinizing hormone(LH) secretion is determined by the following biological studies.

In humans and rodents, castration is well-precedented to permitheightened, persistent GnRH signaling and consequent elevation ofcirculating LH. Thus, a castrated rat model is used to provide a broadindex for measurement of LH inhibition as a marker of test compoundinhibition of the GnRH signaling pathway.

Castrated adult male Sprague-Dawley (SD) rats (150-175 g) were purchasedfrom Janvier (St Berthevin, France). All animals were housed 2 per cagein a temperature-controlled room (22±2° C.) and 50±5% relative humiditywith a 12 hour/12 hour light/dark cycles (lights off at 6 h00 pm). Theanimals were allowed 3 weeks of postoperative recovery prior to study.Animals were handled on a daily basis. Standard diet and tap water wereprovided ad libitum. Animal cage litters were changed once a week. Onthe study day, animals were acclimated to the procedure room for aperiod of one hour prior to the initiation of the experiment.

Compounds of the invention were formulated in 0.5% methyl cellulose.

After basal sampling (TO) a single dose of compounds of the invention orvehicle was administrated orally to rats. Blood samples were thencollected at several time points post dosing (45, 90, 150, 300 and 420minutes). Blood samples were obtained via tail vein bleed, drawn intoEDTA-containing tubes and centrifuged immediately. Plasma samples werecollected and stored in a −80° C. freezer until assayed. Serum LH levelswere determined using radioimmunoassay kit from RIAZEN—Rat LH, Zentech(Liege, Belgium). Baseline was defined as the initial basal bloodsample.

When tested in the castrated male rat model described above, compoundsno 1, 2, 4, 5, 8, 9, 11, 13, 20 and 30 of the invention significantlysuppressed circulating LH levels (statistically significant, p<0.05) ata dose less than or equal to 30 mg/kg).

Effect of Compounds of the Invention on Plasma Testosterone in GonadIntact Male Rats

The study was designed to evaluate the effect of compounds of theinvention on testosterone circulating levels following oraladministration at 3 mg/kg on SD gonad intact male rats.

Briefly the experimental methods used for this study were as follows:

Two groups of non-fasted rats (male, Sprague-Dawley, 200 to 225 g; n=4rats/group) with jugular vein cannulation, were dosed via a single oraladministration of compounds of the invention at 3 mg/kg. The controlgroup was dosed with the vehicle. Compounds of the invention wereprepared in a dose formulation of pyrogen-free water with 0.5%methylcellulose. Blood samples were collected via the catheter implantedin the jugular vein at pre-determined intervals using EDTA-3K asanti-coagulant. Samples were chilled and rapidly processed bycentrifugation to obtain corresponding plasma samples. Testosteronehormone levels were determined by RIA performed on plasma samplescollected for all the groups at 5 minutes before administration (basaltime), and at 45, 90, 150, 300, 480 minutes and 24 hours after dosing.

When tested in the gonad intact male rats, compound no 5 significantlysuppressed plasma testosterone level over the test period as compared tothe vehicle treated group (FIG. 1 ).

Effect of compounds of the invention on prostate weight reduction in aBenign Prostatic Hyperplasia (BPH) rat model. Briefly, adult male ratswere injected daily for four weeks with testosterone to cause anenlargement of the prostate as per methods previously described in theliterature (Scolnick et al., J. Andrology, 1994, 15(4), 287-297; Rick etal., J. Urol., 2012, 187, 1498-1504; see FIG. 2 , Ctrl Neg vs BHP). Ratswere than treated daily for three weeks with compounds of the invention.After 21 days treatment with compounds of the invention at 3, 10 or 30mg/kg (q.d.; PO administration), the ratio of prostate to body weight (gprostate/100 g of body weight) was evaluated as an indicator of BPH.Treated groups were compared to the BPH group (Testosterone-induced BPHgroup followed 21 days of vehicle administration) or to the Controlgroup (Corn oil injection for the induction phase followed by vehicletreatment rather than test compound). Comparison between groups was madeby using One-Way ANOVA followed by Dunnett's test for statisticalanalysis.

When tested in the Benign Prostatic Hyperplasia rat model, compound no5, demonstrated a concentration-response to reduce prostate weight tonormal levels (i.e. levels in rats not exposed to exogenoustestosterone; FIG. 2 ).

Effect of compounds of the invention on Estradiol circulating level infemale rats. The aim of this study was to evaluate the effect ofcompounds of the invention on plasma estradiol levels following oraladministration at 10 mg/kg (b.i.d.) for a period of 10 days in femalerats.

Briefly the experimental methods used for this study were as follows:

Two groups of adult, female rats (Sprague-Dawley, ˜320 g) were treatedin-phase with their individual estrous cycles. Thus, treatment wasstarted in the proestrus phase (coincident with peak estradiol levels,as shown on Day 1 in FIG. 3 ) and rats were dosed twice daily (˜9 h30and 17 h30) by oral administration either with a compound of theinvention at 10 mg/kg or with the vehicle for the control group.Compounds of the invention were prepared in a dose formulation ofpyrogen-free water with 0.5% methylcellulose. Estradiol levels weredetermined for all groups by ELISA performed on plasma samples derivedfrom blood collections taken at 30 minutes before the daily, 9 h30 testarticle administration on all days presented in FIG. 3 .

In vehicle-treated, adult female rats, estradiol peaks are observedevery 4-5 days consistent with the anticipated duration of the ratestrous cycle. Treatment with compound no 5, significantly decreasedestradiol levels over the time-course tracked over two consecutiveestrous cycles. This finding is most apparent in the proestrus phase(i.e. for vehicle group, on Day 5 and Day 9) where estradiol levels risecoincident with ovulation.

In Vivo Assay in OVX Ewes—Activity in Thermoregulation

Experimental Methods: Evaluation of Thermoregulation in OVX Ewe

Ten Corriedale ewes (body weight 56.6±3.4 kg) of 3-4 years of age wereovariectomized according to Standard Operating Procedures, as previouslydescribed (Barker-Gibb, Scott, Boublik, & Clarke, 1995). After 4 monthsrecovery, animals were acclimatised to housing in single pens for aperiod of 7 days with ad libitum access to water and chaffed lucernehay. One day prior to experimentation, the animals received a jugularvein cannula (Dwellcath, Tuta Laboratories, Lane Cove, Australia). Thecannula were kept patent with heparinised saline. On the day of theexperiment, compound no 5 of the present invention was formulated inphysiological saline with 9% 2-hydroxypropyl-p-cyclodextrin at aconcentration of 2 mg/mL. Compound no 5 (1 mg/kg, N=5) or vehicle (N=5)was administered at 11 h00 by intravenous bolus injection at a dosevolume of 0.5 mL/kg through the jugular cannula and the injectedmaterial was flushed into the animal with 5 mL of heparinised saline.Animals were fed at 12 h00. Rectal temperatures were monitored with aprobe at hourly intervals throughout the experiment, starting at 7 h40and concluding at 15 h40.

Results In response to feeding at 12 h00, vehicle-treated animalsexhibited a transient, relative body temperature increase of >0.7° C.measured at 12 h40, consistent with findings previously reported in theliterature (Henry, Dunshea, Gould, & Clarke, 2008).

However, this pyrogenic response to feeding in ovarectomized ewes wasnot observed in any animals treated with compound no 5. Thus, at the 12h40 time point, the body temperature of the vehicle-treated group(39.7±0.3° C.) was significantly (p<0.05) higher than that of thecompound no 5-treated group (38.9±0.2° C.), as presented in FIG. 4 .Graphical data presented as mean±SEM for vehicle-treated versus compoundno 5-treated ewes (N=5/group). Statistical analyses performed by 2-wayANOVA followed by Sidak's Multiple Comparisons Test between treatmentgroups at the indicated time interval, *p<0.05.

Conclusions: Ovariectomy in the ewe causes changes in core bodytemperature considered analogous to menopausal hot flashes (MacLeay,Lehmer, Enns, Mallinckrodt, Bryant, & Turner, 2003) to the extent that atransient, pyrogenic response to feeding is observed (Henry, Dunshea,Gould, & Clarke, 2008). It is herein demonstrated that the compounds ofthe invention protect against this hot flash induced by feeding.

Therefore, the NK-3 receptor antagonists of the invention havetherapeutic utility to protect against hot flashes in clinicalsituations where sex steroids (principally, estrogen in women andtestosterone in men) are compromised, including such disorders as theinduction of hot flashes due to menopause and the induction of hotflashes as a consequence of cancer therapy that lowers sex hormones (forexample, therapy-induced hot flashes in breast, uterine and prostatecancer).

Clinical Evaluation of Compound no 5 for the Treatment of Menopausal HotFlashes

Experimental Methods:

Objectives: The study objective is to evaluate the effect of compound no5 on the severity and frequency of hot flashes in postmenopausal women.

Design and Setting: The Phase 2a clinical trial was conducted in 80patients, divided over 2 treatment groups of 40 patients each. One groupreceived placebo while the other group received 90 mg of compound no 5twice daily (BID) for a period of 12 weeks. The Phase 2a trial wasdouble blind and randomized. This Phase 2a trial was conducted onhealthy menopausal women (40-65 y) experiencing at least 49 moderate orsevere hot flashes or night sweats over a period of 7 consecutive daysin the screening period (maximum of 4 weeks). The study was conducted onan ambulatory basis where patients were asked to visit the clinical siteon the first day of dosing and at weeks 4, 8, 12 during the treatmentperiod with a follow-up visit 2-3 weeks after conclusion of dosing.

Hot flashes were to be reported daily in the morning and the eveningusing an electronic diary tool. These reported events were used tocalculate the Hot Flash Frequency and the Hot Flash Score.

The weekly number of hot flashes was calculated in two ways:cumulatively for all severity grades, and cumulatively but leaving outthe number of mild hot flashes. Hot Flash Frequencies were calculatedfor weeks 4 and 12.

The Hot Flash Score (HFS) is a composite score combining both frequencyand severity. This score is an accepted method to assess the overallseverity of the hot flash burden and is calculated weekly. The score isa general measure of the number and severity of all hot flashes occurredduring a given time period. The Hot Flash Score (based on severity andfrequency) is calculated as follows:

-   -   day-score=(number of mild hot flashes/day×1)+(number of moderate        hot flashes/day×2)+(number of severe hot flashes/day×3)    -   The weekly hot flash score is calculated: Mean HFS day-score        over 1 week    -   Scores were calculated for weeks 4 and 12

Higher scores indicate worse symptoms. There is no maximum score sincethe number of hot flashes does not have an upper limit.

Results: In response to treatment by compound no 5 (90 mg BID) bothScore and Frequency of hot flashes in postmenopausal women weresignificantly reduced in comparison of placebo-controlled group aspresented in Table 5 (Hot Flash Score) and in Table 6 (Hot FlashFrequencies). Data are presented as mean for placebo-treated versuscompound no 5-treated patients (N=40/group). Statistical analysesperformed by 2-way ANOVA.

Table 5 is a table showing the calculated Hot Flashes Score for moderateand severe hot flashes expressed as absolute change from baseline afteroral administration of compound no 5 (90 mg BID) or of a placebo.

Mean Endpoint Visit Compound no5 Placebo P value Hot Flash Baseline29.08 25.92 n.s. Score Week 4 2.96 15.69 <0.0001 Week 12 1.70 13.68<0.0001

Table 6 is a table showing the calculated Hot Flashes Frequency formoderate and severe hot flashes expressed as absolute change frombaseline after oral administration of compound no 5 (90 mg BID) or of aplacebo.

Mean Endpoint Visit Compound no5 Placebo P value Frequency Baseline11.84 10.72 n.s. Week 4 1.35 6.6 <0.0001 Week 12 0.79 5.6 <0.0001

Conclusions:

This well-controlled, Clinical trial study has been sufficiently poweredto provide clear insight into the therapeutic value of compound no 5 forthe treatment of menopausal hot flashes. It is herein demonstrated thatthe compounds of the invention can effectively prevent the occurrence ofmoderate and severe hot flashes in postmenopausal women.

Therefore, the NK-3 receptor antagonists of the invention havetherapeutic utility to protect against hot flashes in clinicalsituations where sex steroids (principally, estrogen in women andtestosterone in men) are compromised, including such disorders as theinduction of hot flashes due to menopause and the induction of hotflashes as a consequence of hormone therapy intentionally lowering thelevel of sex hormones (for example, therapy-induced hot flashes inbreast, uterine and prostate cancer).

Clinical Evaluation of compound no 5 for the Treatment of PolyCysticOvary Syndrome (PCOS)

Experimental Methods:

Objectives: The study objectives are to evaluate the effect of compoundno 5 on the serum levels of Total Testosterone (TT), Luteinizing Hormone(LH), Follicle Stimulating Hormone (FSH) and LH:FSH ratio after 12 weeksof treatment.

Design and Setting: The Phase 2a clinical trial was conducted in 48patients, divided over 2 treatment groups of 24 patients each. One groupreceived placebo while the other group received 180 mg of compound no 5once daily (QD) for a period of 12 weeks. The Phase 2a trial was doubleblind and randomized. This Phase 2a trial was conducted on women (18-45y) diagnosed with PCOS as per the Rotterdam Criteria and demonstratingbiochemical hyperandrogenism, defined as TT>50 ng/dL [1.7 nmol/L] atscreening. The study was conducted on an ambulatory basis where patientswere asked to visit the clinical site on the first day of dosing and atweeks 3, 6, 9 and 12 during the treatment period with a follow-up visit2-3 weeks after conclusion of dosing.

Blood draws for LH, FSH and TT were taken every visit between 2 and 8hours after drug intake (baseline and week 3-6-12). At week 9 the bloodsamples were taken in the morning before drug intake (i.e. at trough PKconcentrations for compound no 5). These blood draws were the basis forassessing the primary (TT) and secondary (LH, FSH, LH:FSH ratio)endpoints. The primary endpoint of Total Testosterone was measuredaccording to GLP using an LC-MS/MS method.

PCOS is typically characterized by excessive ovarian androgenproduction, failure of ovulation, and slightly enlarged ovaries withnumerous peripheral small follicles that appear as cysts. The disorderis commonly accompanied by infertility. Typically, the clinical featuresof PCOS are associated with hypersecretion of LH and androgens (TT) butwith normal serum concentrations of FSH hormone. Laboratory examinationsreveal elevated TT levels in about 50% of the patients, accompanied byan elevated LH:FSH ratio (>2) due to the imbalanced secretion of bothhormones (a ratio of 1 is considered normal).

Results: In response to treatment by compound no 5 (180 mg QD) both TTand LH:FSH were significantly reduced in comparison ofplacebo-controlled group as presented in Table 7 (TT) and in Table 8(LH:FSH). Data are presented as mean for placebo-treated versus compoundno 5-treated patients (N=24/group). Statistical analyses performed by2-way ANOVA comparing placebo to treatment. The significant decrease inthe LH:FSH ratio reflects the observed significant decrease in LH withpreserved FSH secretion.

The evolution of the primary endpoint (decrease in TT) during the courseof the study is presented in FIG. 5 , showing a clear decreasing of TTduring the 12 weeks of dosing and a clear rebound effect on circulatingandrogen levels after withdrawal from treatment, indicative of a directrelationship between drug intake and pharmacodynamic effect.

Table 7 is a table showing the actual values for Total Testosteronelevels at baseline and after oral administration of compound no 5 (180mg QD) or placebo.

Mean Endpoint Visit Compound no5 Placebo P value Total Baseline 2.162.01 n.s. Testosterone Week 6 1.41 1.91 * <0.05 (nmol/L) Week 12 1.391.92 * <0.05

Table 8 is a table showing the calculated actual values for LH:FSH ratioafter oral administration of compound no 5 (180 mg QD) or placebo.

Mean Endpoint Visit Compound no5 Placebo P value LH:FSH Baseline 2.672.60 n.s. Week 6 1.19 2.45 *** <0.001 Week 12 1.16 2.33 *** <0.001

Conclusions:

This well-controlled, clinical trial study has been sufficiently poweredto provide clear insight into the therapeutic value of compound no 5 forthe treatment of PCOS. It is herein demonstrated that the compounds ofthe invention can effectively restore the hormonal balance of LH and FSHand decrease the testosterone levels in women with PCOS.

Therefore, the NK-3 receptor antagonists of the invention havetherapeutic utility to restore the hormonal balance in clinicalsituations where the normal homeostasis of gonadotrophins (principally,luteinising hormone) is compromised, including disorders affecting theHypothalamic-Pituitary-Gonadotropic function, such as the PCOS.

The invention claimed is:
 1. A method for preventing and/or treatingmoderate hot flashes or severe hot flashes in a patient, wherein themethod comprises administering to the patient in need thereof for atleast four weeks a pharmaceutically effective amount of the followingcompound:

wherein the frequency of moderate hot flashes or severe hot flashes inthe patient after at least four weeks of treatment is reduced comparedto the frequency of moderate hot flashes or severe hot flashes in thepatient before at least four weeks of treatment.
 2. The method accordingto claim 1, wherein the moderate hot flashes or severe hot flashes arerelated to a condition selected from the group consisting of aperimenopausal condition, a menopausal condition, and a postmenopausalcondition, or a combination thereof.
 3. The method according to claim 1,wherein the moderate hot flashes or severe hot flashes are a consequenceof hormone therapy which intentionally lowers the level of sex hormones.4. The method according to claim 3, wherein the moderate hot flashes orsevere hot flashes are selected from the group consisting oftherapy-induced moderate hot flashes in breast cancer, therapy-inducedsevere hot flashes in breast cancer, therapy-induced moderate hotflashes in uterine cancer, therapy-induced severe hot flashes in uterinecancer, therapy-induced moderate hot flashes in prostate cancer, andtherapy-induced sever hot flashes in prostate cancer.
 5. A method forpreventing and/or treating moderate hot flashes or severe hot flashes ina patient, wherein the method comprises administering to the patient inneed thereof for at least four weeks a pharmaceutically effective amountof the following compound:

wherein the severity of moderate hot flashes or severe hot flashes inthe patient after at least four weeks of treatment is reduced comparedto the severity of moderate hot flashes or severe hot flashes in thepatient before at least four weeks of treatment.
 6. The method accordingto claim 5, wherein the moderate hot flashes or severe hot flashes arerelated to a condition selected from the group consisting of aperimenopausal condition, a menopausal condition, and a postmenopausalcondition, or a combination thereof.
 7. The method according to claim 5,wherein the moderate hot flashes or severe hot flashes are a consequenceof hormone therapy which intentionally lowers the level of sex hormones.8. The method according to claim 7, wherein the moderate hot flashes orsevere hot flashes are selected from the group consisting oftherapy-induced moderate hot flashes in breast cancer, therapy-inducedsevere hot flashes in breast cancer, therapy-induced moderate hotflashes in uterine cancer, therapy-induced severe hot flashes in uterinecancer, therapy-induced moderate hot flashes in prostate cancer, andtherapy-induced sever hot flashes in prostate cancer.